- Email: [email protected]
Myocardial energetics: Still only the tip of an iceberg
Heart, Lung and Circulation 2003; 12: 3–6
Editorial Myocardial Energetics: Still Only the Tip of an Iceberg Heinrich Taegtmeyer, MD, DPhil The University of Texas Houston Medical School, Department of Medicine, Division of Cardiology, Houston, TX, USA
‘When studying a biological phenomenon, it is always important to examine the whole process and not merely a fragment in a damaged tissue.’ – Hans Krebs, 19811
T
he heart adapts to acute changes in its workload through acute changes in metabolic fluxes that exactly match rates of energy production with rates of energy utilisation.2–5 How the heart muscle achieves this balance of energy production and utilisation remains a mystery, despite more than half a century of research on this topic. Investigators have often been frustrated by the limitations in assessing the transformation of energy in a biological system,6 and the heart is no exception. Acute adaptation to environmental stimuli leads to chronic adaptation in the form of metabolic remodelling,7,8 and maladaptation in the form of pathological metabolic remodelling. A common feature of remodelling is the re-emergence of the constitutively expressed fetal gene program.9 At a post-transcriptional level, the distributive system of energy transformation has to respond efficiently to the constant changes in its environment. In her elegant review, Dr Seymour takes an optimistic view and proposes nuclear magnetic resonance (NMR) as an extremely powerful technique to investigate abnormalities of energy metabolism in the failing heart. Important pieces of an elaborate system of checks and balances are coming together. However, the picture is still far from complete. This commentary attempts to offer a somewhat broader view of cardiac energetics as they relate to energy substrate metabolism.
See related article p. 25
The Iceberg of Cardiac Energetics: From Substrates to Adenosine Triphosphate Since the discovery of the energy-rich phosphate bond as a principle of energy transformation in biological systems,10 adenosine triphosphate (ATP) has been at the centre of energetics. This view is, however, far too restrictive in a system that defines energy as the capacity for doing work. In such a system, ATP is more like the tip of an iceberg while the whole of energy metabolism from substrates to ATP is the iceberg itself (Fig. 1). The analogy of the iceberg replaces the maze of metabolic pathways depicted in biochemistry textbooks. Function and metabolism of the heart are inextricably linked. The heart derives its energy for contraction from the co-ordinated and regulated breakdown of energyproviding substrates, the generation of reducing equivalents and the oxidative phosphorylation of adenosine diphosphate (ADP) in the respiratory chain. The rate of ATP turnover is measured indirectly from the rate of O2 consumption. In this system it becomes rapidly apparent that the rate of ATP turnover far exceeds the amount of ATP available for contraction. A few principles of energy transfer in the heart should be considered. Because of built-in mechanisms that select the most efficient substrate for a given physiological environment, the heart is a true metabolic omnivore. In the postprandial state, when fatty acid levels in the blood are high and insulin levels are low, fatty acids are the main fuels for respiration.11 When it was discovered that fatty acids suppress glucose oxidation, chiefly at the level of the pyruvate dehydrogenase complex, myocardial fuel ecomomy became the focus of biochemical investigation.12 Conversely, glucose also suppresses fatty acid oxidation,3 and glucose and/or glycogen become the main fuel for respiration of the stressed heart.4 In short, fuel metabolism of the heart is
4
H. Taegtmeyer Editorial
Figure 1. The iceberg analogy. Like the maze of metabolic maps, the iceberg analogy is nothing more than a perception of reality. ATP, adenosine triphosphate. highly regulated, and this system of regulation allows the heart to respond to changes in substrate availability, circulating hormones (such as insulin or catecholamines), coronary flow and workload by selecting the ‘right’ substrate at the right moment. To put it more simply: the heart is never short of fuel to burn as long as coronary flow is not curtailed. The most efficient way to transfer energy is through a series of moiety-conserved cycles.11,13 We have argued that one mechanism for defective energy transfer in the heart is the result of an impairment or collapse of moiety-conserved cycles, including the citric acid cycle.14,15 Conversely, replenishing defective moieties through anaplerotic reactions can restore contractile function of the heart.16,17
Control versus Regulation The adaptive responses of the heart to changes in its environment are subject to both control and regulation. The metabolic control theory is careful to distinguish the two terms because the former refers to environmental factors affecting the response of the cell, while the latter refers to properties of the cell itself. In other words, control refers to the power to change the state of metabolism in response to external stimuli, and regulation refers to the performance of the metabolic system.18 How are regulatory sites in a metabolic pathway or cycle identified? The ‘crossover-theorem’ of Williams and Chance (1955)19 states that metabolites accumulate upstream and disappear downstream from a regulated enzyme, or vice versa. The four major regulatory mechanisms are enzyme amount (Vmax), allosteric regulator power, covalent modification and cofactor availability.
Heart, Lung and Circulation 2003; 12
After decades of measuring steady state metabolite concentrations in the freeze-clamped heart, physiologists recognised more and more the lack of correlation between tissue metabolite levels and metabolic flux. They observed that the rate of energy conversion is not always tied to the concentrations of certain metabolic intermediates in a pathway (notable exceptions are metabolically generated regulators of enzyme activity such as fructose 2,6-bisphosphate, or malonyl-CoA). Other approaches have been introduced. The most prominent are simultaneous measurements of enzyme activities in vitro and metabolic rates in the intact organ,20 and, more recently, the constitutive or conditional overexpression or deletion of key regulatory enzymes in genetically manipulated mouse models of cardiac energy metabolism21–25 and in signalling pathways of insulin action.26,27 However, caution must be exercised when interpreting data from such models. The overexpression or deletion of a single protein may cause pleiotropic effects in a variety of enzymes and pathways not directly related to the one under investigation.
Nutrient Sensing: Metabolic Signals as Mediators of Transcriptional Regulation in the Heart We have recently proposed that altered glucose homeostasis within the cardiomyocyte acts as a central mechanism for the regulation of gene expression in response to an altered environment28 (Fig. 2). In preliminary studies we suggested that glucose, or one of its metabolites, induces myosin heavy chain isoform switches both in vitro and in vivo. Relatively little is known about how changes in glucose metabolites are ultimately sensed by the nuclear transcriptional machinery.29 A model of glucose-mediated transcriptional regulation is the carbohydrate-sensitive cis-regulatory element (ChoRE). Upstream stimulatory factor (USF) binds as a dimer to this site, but the exact way by which glucose influences USF-mediated transcription is still not known. Nonetheless, the intriguing possibility exists that glucose-dependent transcriptional events not only affect transcription of metabolic genes, but also of genes encoding sarcomeric and Ca2+-cycling proteins. We have recently found that the addition of glutamine as a major nutrient to cultured neonatal rat cardiomyocytes produced an increase in myocyte size.30 The cellular response is associated with increased mRNA transcript levels encoding α-myosin heavy chain, cardiac α-actin and the metabolic enzymes carnitine palmitoyl transferase-1 (CPT-1) and muscle adenylosuccinate synthetase 1 (Adss 1). The induction of Adss 1 was mediated through protein kinase A (PKA) and mammalian target
Heart, Lung and Circulation 2003; 12
H. Taegtmeyer Editorial
5
failing heart36,37 without a sufficiently high compensatory increase in glucose oxidation.38 Reactivation of fatty acid metabolism genes in the adapted hypertrophied rat heart also leads to contractile dysfunction due to impaired energy transfer.33 In the failing human heart, glucose transporter 1 (GLUT1) expression is severely down-regulated as well as the nuclear receptor PPARα, the master switch for transcriptional regulation of fatty acid metabolism enzymes.35 Thus, there is evidence that two key regulators of glucose and fatty acid metabolism are down-regulated when the human heart fails.
Outlook
Figure 2. Hypothetical schematic of nutrient sensing and metabolic regulation of gene expression in the heart. of rapamycin (mTOR) pathways, implicating glutamine as a major regulator of cardiac gene expression. Other examples for nutrient sensing include fatty acid regulated transcriptional regulation through the peroxisome proliferator activated receptor (PPAR) and the PPAR cis-regulatory element (PPRE). This subject has been reviewed elsewhere.8,29,31 Here it suffices to state that PPARα is probably a major switch that regulates fatty acid and glucose metabolism.
Defective Energy Metabolism in Heart Failure To recapitulate once more: metabolism is not an innocent bystander when it comes to cardiac gene expression. Metabolic adaptation, switching from fat to glucose, results in increased efficiency of the heart.32 Metabolic maladaptation with impaired substrate oxidation results in decreased efficiency of the heart.33 The heart fails in the midst of plenty34 because it can not utilise the abundant substrate supplied to it. With progression of the metabolic remodelling process from adaptation to maladaptation, regulated metabolic pathways become dysregulated pathways, and the failing heart loses its ability to switch to the most efficient fuel for energy production. Energy transfer becomes impaired at the level of intermediary metabolism.35 Most importantly, the capacity for oxidising long-chain fatty acids is impaired in the
Metabolism is an integral part of cardiac structure and function. The plasticity of metabolic pathways is tied to efficient transfer of energy from substrates to ATP. Control and regulation of energy substrate metabolism in the heart is even more complex than the complex metabolic maps suggest. We are now faced with a dilemma. There are a multitude of powerful invasive and noninvasive techniques to interrogate metabolic pathways but a dwindling number of clinical researchers who appreciate the complexity of energy transfer in the heart and are willing to explore new knowledge for the benefit of patients with heart failure. It is fitting that we remember though, that we are still dealing only with the tip of an iceberg.
Acknowledgements I thank Stacey Vigil for her help with the preparation of the manuscript. Work in my laboratory is supported by the National Heart, Lung and Blood Institute of the United States Public Health Service.
References 1. Krebs HA, Martin A. Hans Krebs: Reminiscences and Reflections. Clarendon Press, Oxford, 1981. 2. Neely JR, Liebermeister H, Battersby EJ, Morgan HE. Effect of pressure development on oxygen consumption by isolated rat heart. Am. J. Physiol. 1967; 212: 804–14. 3. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy providing substrates in the isolated working rat heart. Biochem. J. 1980; 186: 701–11. 4. Goodwin GW, Taylor CS, Taegtmeyer H. Regulation of energy metabolism of the heart during acute increase in heart work. J. Biol. Chem. 1998; 273: 29530–39. 5. Balaban RS. Cardiac energy metabolism homeostasis: role of cytosolic calcium. J. Mol. Cell Cardiol. 2002; 34: 1259–71. 6. Srere P. Citric acid cycle redux. TIBS 1990; 15: 411–12. 7. Taegtmeyer H, Dietze GJ. A symposium: From increased energy metabolism to cardiac hypertrophy and failure: Mediators and molecular mechanisms. Am. J. Cardiol. 1999; 83: 1H–98H.
6
H. Taegtmeyer Editorial
8. Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc. Med. 2000; 10: 238–45. 9. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation 2001; 104: 2923–31. 10. Lipmann F. Metabolic generation and utilization of phosphate bond energy. Adv. Enzymol. 1941; 1: 99–165. 11. Taegtmeyer H. Energy metabolism of the heart: From basic concepts to clinical applications. Curr. Prob. Cardiol. 1994; 19: 57–116. 12. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1: 785–9. 13. Baldwin JE, Krebs HA. The evolution of metabolic cycles. Nature 1981; 291: 381–2. 14. Taegtmeyer H, Passmore JM. Defective energy metabolism of the heart in diabetes. Lancet 1985; 1: 139–41. 15. Taegtmeyer H. Is there a rationale for glucose–insulin– potassium therapy in acute myocardial infarction? Cardiol. Rev. 1995; 3: 307–13. 16. Russell RR, Taegtmeyer H. Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am. J. Physiol. 1991; 261: H1756–62. 17. Bradamante S, Marchesani A, Barenghi L, Paracchini L, de Jonge R, de Jonge J. Glycogen turnover and anaplerosis in preconditioned rat hearts. Biochim. Biophys. Acta 2000; 1502: 363–79. 18. Fell D. Understanding the Control of Metabolism. Portland Press, Miami, 1997. 19. Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J. Biol. Chem. 1955; 217: 409–27. 20. Cooney GJ, Taegtmeyer H, Newsholme EA. Tricarboxylic acid cycle flux and enzyme activities in the isolated working rat heart. Biochem. J. 1981; 200: 701–3. 21. Abel ED, Kaulbach HC, Tian R et al. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J. Clin. Invest. 1999; 104: 1703–14. 22. Liao R, Mohit J, Lei C et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure due to pressure-overload in mice. Circulation 2002; 106: 2125–31. 23. Finck BN, Lehman JJ, Leone TC et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J. Clin. Invest. 2002; 109: 121–30. 24. Liang Q, Donthi R., Kralik P, Epstein P. Elevated hexokinase increases cardiac glycolysis in transgenic mice. Cardiovasc. Res. 2002; 53: 423–30.
Heart, Lung and Circulation 2003; 12
25. Taegtmeyer H. Switching metabolic genes to build a better heart. Circulation 2002; 106: 2043–5. 26. Belke DD, Betuing S, Tuttle MJ et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J. Clin. Invest. 2002; 109: 629–39. 27. Matsui T, Li L, Wu J et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 2002; 277: 22896–901. 28. Young ME, Guthrie P, Stepkowski S, Taegtmeyer H. Glucose regulation of sarcomeric protein gene expression in the rat heart. J. Molec. Cell Cardiol. 2001; A181. 29. van Bilsen M, Van der Vusse GJ, Reneman RS. Transcriptional regulation of metabolic processes: implications for cardiac metabolism. Pflugers Arch. 1998; 437: 2–14. 30. Xia Y, Wen HY, Young ME, Guthrie PH, Taegtmeyer H, Kellems RE. Mammalian target of rapamycin and protein kinase a signaling mediate the cardiac transcriptional response to glutamine. J. Biol. Chem. 2003; 278: 13 143–50. 31. Kelly DP. Peroxisome proliferator-activated receptor alpha as a genetic determinant of cardiac hypertrophic growth: Culprit or innocent bystander? Circulation 2002; 105: 1025–7. 32. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H1345–51. 33. Young ME, Laws FA, Goodwin GW, Taegtmeyer H. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J. Biol. Chem. 2001; 276: 44390–95. 34. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation 2002; 105: 1861–70. 35. Razeghi P, Young ME, Ying J et al. Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading. Cardiology 2002; 97: 203–9. 36. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996; 94: 2837–42. 37. Osorio J, Stanley W, Linke A et al. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 2002; 106: 606–12. 38. Davila-Roman VG, Vedala G, Herrero P et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 2002; 40: 271–7.
Editorial Myocardial Energetics: Still Only the Tip of an Iceberg Heinrich Taegtmeyer, MD, DPhil The University of Texas Houston Medical School, Department of Medicine, Division of Cardiology, Houston, TX, USA
‘When studying a biological phenomenon, it is always important to examine the whole process and not merely a fragment in a damaged tissue.’ – Hans Krebs, 19811
T
he heart adapts to acute changes in its workload through acute changes in metabolic fluxes that exactly match rates of energy production with rates of energy utilisation.2–5 How the heart muscle achieves this balance of energy production and utilisation remains a mystery, despite more than half a century of research on this topic. Investigators have often been frustrated by the limitations in assessing the transformation of energy in a biological system,6 and the heart is no exception. Acute adaptation to environmental stimuli leads to chronic adaptation in the form of metabolic remodelling,7,8 and maladaptation in the form of pathological metabolic remodelling. A common feature of remodelling is the re-emergence of the constitutively expressed fetal gene program.9 At a post-transcriptional level, the distributive system of energy transformation has to respond efficiently to the constant changes in its environment. In her elegant review, Dr Seymour takes an optimistic view and proposes nuclear magnetic resonance (NMR) as an extremely powerful technique to investigate abnormalities of energy metabolism in the failing heart. Important pieces of an elaborate system of checks and balances are coming together. However, the picture is still far from complete. This commentary attempts to offer a somewhat broader view of cardiac energetics as they relate to energy substrate metabolism.
See related article p. 25
The Iceberg of Cardiac Energetics: From Substrates to Adenosine Triphosphate Since the discovery of the energy-rich phosphate bond as a principle of energy transformation in biological systems,10 adenosine triphosphate (ATP) has been at the centre of energetics. This view is, however, far too restrictive in a system that defines energy as the capacity for doing work. In such a system, ATP is more like the tip of an iceberg while the whole of energy metabolism from substrates to ATP is the iceberg itself (Fig. 1). The analogy of the iceberg replaces the maze of metabolic pathways depicted in biochemistry textbooks. Function and metabolism of the heart are inextricably linked. The heart derives its energy for contraction from the co-ordinated and regulated breakdown of energyproviding substrates, the generation of reducing equivalents and the oxidative phosphorylation of adenosine diphosphate (ADP) in the respiratory chain. The rate of ATP turnover is measured indirectly from the rate of O2 consumption. In this system it becomes rapidly apparent that the rate of ATP turnover far exceeds the amount of ATP available for contraction. A few principles of energy transfer in the heart should be considered. Because of built-in mechanisms that select the most efficient substrate for a given physiological environment, the heart is a true metabolic omnivore. In the postprandial state, when fatty acid levels in the blood are high and insulin levels are low, fatty acids are the main fuels for respiration.11 When it was discovered that fatty acids suppress glucose oxidation, chiefly at the level of the pyruvate dehydrogenase complex, myocardial fuel ecomomy became the focus of biochemical investigation.12 Conversely, glucose also suppresses fatty acid oxidation,3 and glucose and/or glycogen become the main fuel for respiration of the stressed heart.4 In short, fuel metabolism of the heart is
4
H. Taegtmeyer Editorial
Figure 1. The iceberg analogy. Like the maze of metabolic maps, the iceberg analogy is nothing more than a perception of reality. ATP, adenosine triphosphate. highly regulated, and this system of regulation allows the heart to respond to changes in substrate availability, circulating hormones (such as insulin or catecholamines), coronary flow and workload by selecting the ‘right’ substrate at the right moment. To put it more simply: the heart is never short of fuel to burn as long as coronary flow is not curtailed. The most efficient way to transfer energy is through a series of moiety-conserved cycles.11,13 We have argued that one mechanism for defective energy transfer in the heart is the result of an impairment or collapse of moiety-conserved cycles, including the citric acid cycle.14,15 Conversely, replenishing defective moieties through anaplerotic reactions can restore contractile function of the heart.16,17
Control versus Regulation The adaptive responses of the heart to changes in its environment are subject to both control and regulation. The metabolic control theory is careful to distinguish the two terms because the former refers to environmental factors affecting the response of the cell, while the latter refers to properties of the cell itself. In other words, control refers to the power to change the state of metabolism in response to external stimuli, and regulation refers to the performance of the metabolic system.18 How are regulatory sites in a metabolic pathway or cycle identified? The ‘crossover-theorem’ of Williams and Chance (1955)19 states that metabolites accumulate upstream and disappear downstream from a regulated enzyme, or vice versa. The four major regulatory mechanisms are enzyme amount (Vmax), allosteric regulator power, covalent modification and cofactor availability.
Heart, Lung and Circulation 2003; 12
After decades of measuring steady state metabolite concentrations in the freeze-clamped heart, physiologists recognised more and more the lack of correlation between tissue metabolite levels and metabolic flux. They observed that the rate of energy conversion is not always tied to the concentrations of certain metabolic intermediates in a pathway (notable exceptions are metabolically generated regulators of enzyme activity such as fructose 2,6-bisphosphate, or malonyl-CoA). Other approaches have been introduced. The most prominent are simultaneous measurements of enzyme activities in vitro and metabolic rates in the intact organ,20 and, more recently, the constitutive or conditional overexpression or deletion of key regulatory enzymes in genetically manipulated mouse models of cardiac energy metabolism21–25 and in signalling pathways of insulin action.26,27 However, caution must be exercised when interpreting data from such models. The overexpression or deletion of a single protein may cause pleiotropic effects in a variety of enzymes and pathways not directly related to the one under investigation.
Nutrient Sensing: Metabolic Signals as Mediators of Transcriptional Regulation in the Heart We have recently proposed that altered glucose homeostasis within the cardiomyocyte acts as a central mechanism for the regulation of gene expression in response to an altered environment28 (Fig. 2). In preliminary studies we suggested that glucose, or one of its metabolites, induces myosin heavy chain isoform switches both in vitro and in vivo. Relatively little is known about how changes in glucose metabolites are ultimately sensed by the nuclear transcriptional machinery.29 A model of glucose-mediated transcriptional regulation is the carbohydrate-sensitive cis-regulatory element (ChoRE). Upstream stimulatory factor (USF) binds as a dimer to this site, but the exact way by which glucose influences USF-mediated transcription is still not known. Nonetheless, the intriguing possibility exists that glucose-dependent transcriptional events not only affect transcription of metabolic genes, but also of genes encoding sarcomeric and Ca2+-cycling proteins. We have recently found that the addition of glutamine as a major nutrient to cultured neonatal rat cardiomyocytes produced an increase in myocyte size.30 The cellular response is associated with increased mRNA transcript levels encoding α-myosin heavy chain, cardiac α-actin and the metabolic enzymes carnitine palmitoyl transferase-1 (CPT-1) and muscle adenylosuccinate synthetase 1 (Adss 1). The induction of Adss 1 was mediated through protein kinase A (PKA) and mammalian target
Heart, Lung and Circulation 2003; 12
H. Taegtmeyer Editorial
5
failing heart36,37 without a sufficiently high compensatory increase in glucose oxidation.38 Reactivation of fatty acid metabolism genes in the adapted hypertrophied rat heart also leads to contractile dysfunction due to impaired energy transfer.33 In the failing human heart, glucose transporter 1 (GLUT1) expression is severely down-regulated as well as the nuclear receptor PPARα, the master switch for transcriptional regulation of fatty acid metabolism enzymes.35 Thus, there is evidence that two key regulators of glucose and fatty acid metabolism are down-regulated when the human heart fails.
Outlook
Figure 2. Hypothetical schematic of nutrient sensing and metabolic regulation of gene expression in the heart. of rapamycin (mTOR) pathways, implicating glutamine as a major regulator of cardiac gene expression. Other examples for nutrient sensing include fatty acid regulated transcriptional regulation through the peroxisome proliferator activated receptor (PPAR) and the PPAR cis-regulatory element (PPRE). This subject has been reviewed elsewhere.8,29,31 Here it suffices to state that PPARα is probably a major switch that regulates fatty acid and glucose metabolism.
Defective Energy Metabolism in Heart Failure To recapitulate once more: metabolism is not an innocent bystander when it comes to cardiac gene expression. Metabolic adaptation, switching from fat to glucose, results in increased efficiency of the heart.32 Metabolic maladaptation with impaired substrate oxidation results in decreased efficiency of the heart.33 The heart fails in the midst of plenty34 because it can not utilise the abundant substrate supplied to it. With progression of the metabolic remodelling process from adaptation to maladaptation, regulated metabolic pathways become dysregulated pathways, and the failing heart loses its ability to switch to the most efficient fuel for energy production. Energy transfer becomes impaired at the level of intermediary metabolism.35 Most importantly, the capacity for oxidising long-chain fatty acids is impaired in the
Metabolism is an integral part of cardiac structure and function. The plasticity of metabolic pathways is tied to efficient transfer of energy from substrates to ATP. Control and regulation of energy substrate metabolism in the heart is even more complex than the complex metabolic maps suggest. We are now faced with a dilemma. There are a multitude of powerful invasive and noninvasive techniques to interrogate metabolic pathways but a dwindling number of clinical researchers who appreciate the complexity of energy transfer in the heart and are willing to explore new knowledge for the benefit of patients with heart failure. It is fitting that we remember though, that we are still dealing only with the tip of an iceberg.
Acknowledgements I thank Stacey Vigil for her help with the preparation of the manuscript. Work in my laboratory is supported by the National Heart, Lung and Blood Institute of the United States Public Health Service.
References 1. Krebs HA, Martin A. Hans Krebs: Reminiscences and Reflections. Clarendon Press, Oxford, 1981. 2. Neely JR, Liebermeister H, Battersby EJ, Morgan HE. Effect of pressure development on oxygen consumption by isolated rat heart. Am. J. Physiol. 1967; 212: 804–14. 3. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy providing substrates in the isolated working rat heart. Biochem. J. 1980; 186: 701–11. 4. Goodwin GW, Taylor CS, Taegtmeyer H. Regulation of energy metabolism of the heart during acute increase in heart work. J. Biol. Chem. 1998; 273: 29530–39. 5. Balaban RS. Cardiac energy metabolism homeostasis: role of cytosolic calcium. J. Mol. Cell Cardiol. 2002; 34: 1259–71. 6. Srere P. Citric acid cycle redux. TIBS 1990; 15: 411–12. 7. Taegtmeyer H, Dietze GJ. A symposium: From increased energy metabolism to cardiac hypertrophy and failure: Mediators and molecular mechanisms. Am. J. Cardiol. 1999; 83: 1H–98H.
6
H. Taegtmeyer Editorial
8. Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc. Med. 2000; 10: 238–45. 9. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation 2001; 104: 2923–31. 10. Lipmann F. Metabolic generation and utilization of phosphate bond energy. Adv. Enzymol. 1941; 1: 99–165. 11. Taegtmeyer H. Energy metabolism of the heart: From basic concepts to clinical applications. Curr. Prob. Cardiol. 1994; 19: 57–116. 12. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1: 785–9. 13. Baldwin JE, Krebs HA. The evolution of metabolic cycles. Nature 1981; 291: 381–2. 14. Taegtmeyer H, Passmore JM. Defective energy metabolism of the heart in diabetes. Lancet 1985; 1: 139–41. 15. Taegtmeyer H. Is there a rationale for glucose–insulin– potassium therapy in acute myocardial infarction? Cardiol. Rev. 1995; 3: 307–13. 16. Russell RR, Taegtmeyer H. Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am. J. Physiol. 1991; 261: H1756–62. 17. Bradamante S, Marchesani A, Barenghi L, Paracchini L, de Jonge R, de Jonge J. Glycogen turnover and anaplerosis in preconditioned rat hearts. Biochim. Biophys. Acta 2000; 1502: 363–79. 18. Fell D. Understanding the Control of Metabolism. Portland Press, Miami, 1997. 19. Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J. Biol. Chem. 1955; 217: 409–27. 20. Cooney GJ, Taegtmeyer H, Newsholme EA. Tricarboxylic acid cycle flux and enzyme activities in the isolated working rat heart. Biochem. J. 1981; 200: 701–3. 21. Abel ED, Kaulbach HC, Tian R et al. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J. Clin. Invest. 1999; 104: 1703–14. 22. Liao R, Mohit J, Lei C et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure due to pressure-overload in mice. Circulation 2002; 106: 2125–31. 23. Finck BN, Lehman JJ, Leone TC et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J. Clin. Invest. 2002; 109: 121–30. 24. Liang Q, Donthi R., Kralik P, Epstein P. Elevated hexokinase increases cardiac glycolysis in transgenic mice. Cardiovasc. Res. 2002; 53: 423–30.
Heart, Lung and Circulation 2003; 12
25. Taegtmeyer H. Switching metabolic genes to build a better heart. Circulation 2002; 106: 2043–5. 26. Belke DD, Betuing S, Tuttle MJ et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J. Clin. Invest. 2002; 109: 629–39. 27. Matsui T, Li L, Wu J et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 2002; 277: 22896–901. 28. Young ME, Guthrie P, Stepkowski S, Taegtmeyer H. Glucose regulation of sarcomeric protein gene expression in the rat heart. J. Molec. Cell Cardiol. 2001; A181. 29. van Bilsen M, Van der Vusse GJ, Reneman RS. Transcriptional regulation of metabolic processes: implications for cardiac metabolism. Pflugers Arch. 1998; 437: 2–14. 30. Xia Y, Wen HY, Young ME, Guthrie PH, Taegtmeyer H, Kellems RE. Mammalian target of rapamycin and protein kinase a signaling mediate the cardiac transcriptional response to glutamine. J. Biol. Chem. 2003; 278: 13 143–50. 31. Kelly DP. Peroxisome proliferator-activated receptor alpha as a genetic determinant of cardiac hypertrophic growth: Culprit or innocent bystander? Circulation 2002; 105: 1025–7. 32. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H1345–51. 33. Young ME, Laws FA, Goodwin GW, Taegtmeyer H. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J. Biol. Chem. 2001; 276: 44390–95. 34. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation 2002; 105: 1861–70. 35. Razeghi P, Young ME, Ying J et al. Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading. Cardiology 2002; 97: 203–9. 36. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996; 94: 2837–42. 37. Osorio J, Stanley W, Linke A et al. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 2002; 106: 606–12. 38. Davila-Roman VG, Vedala G, Herrero P et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 2002; 40: 271–7.