Abstract
The function of the heart is defined by its ability to deliver adequate cardiac output to meet the requirements of the body both at rest and with exertion. To fill this role, the heart demonstrates an impressive capacity to tightly regulate energy generation and consumption. Energy production and transfer within cardiac myocytes primarily relies on the process of oxidative phosphorylation. In the failing heart, there is an imbalance between the work of the cardiac system and the energy required to generate this work. This presence of this mismatch has given rise to the concept known as the energy starvation theory. This concept encapsulates observations such as perturbed substrate consumption, insufficient energy transfer and ingestion, reduced substrate and oxygen availability, and diminished energy production in the failing heart. Diminished available cellular energy may further result from a reduction in the biosynthesis of mitochondria and their protein synthesis and from global cellular architectural disarray. In essence, the energy starvation theory posits that cardiac pump function declines due to a reduction in oxygen and substrate availability, and thus leads to a total body starvation of systemic energy. This novel cognitive framework has led to encouraging new directions in a “metabolic therapeutic approach” for the failing heart.
Similar content being viewed by others
References
Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145
Ventura-Clapier R, Garnier A, Veksler V (2004) Energy metabolism in heart failure. J Physiol 555:1–13
Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151
Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011) Bioenergetics of the failing heart. Biochim Biophy Acta 1813:1360–1372
Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40:1271–1296
Cotter DG, Schugar RC, Crawford PA (2013) Ketone body metabolism and cardiovascular diseases. Am J Physiol Heart Circ Physiol 304:H1060–H1076
Drake KJ, Sidorov VY, McGuinness OP, Wasserman DH, Wikswo JP (2012) Amino acids as metabolic substrates during cardiac ischemia. Exp Bio Med 237:1369–1378
Taegtmeyer H (2002) Switching metabolic genes to build a better heart. Circulation 106:2043–2045
Rimbaud S et al (2009) Stimulus specific changes of energy metabolism in hypertrophied heart. J Mol Cell Cardiol 46:952–959
Osorio JC et al (2002) Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 106:606–612
Lei B et al (2004) Paradoxical down-regulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol Cell Cardiol 36:567–576
Razeghi P et al (2001) Metabolic gene expression in fetal and failing human heart. Circulation 104:2923–2931
Leong HS, Brownsey RW, Kulpa JE, Allard MF (2003) Glycolysis and pyruvate oxidation in cardiac hypertrophy—why so unbalanced? Comp Biochem Physiol Part A Mole Integr Physiol 135:499–513
Benard G et al (2010) Multisite control and regulation of mitochondrial energy production. Biochim Biophys Acta 1797:698–709
Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis. The central role of PGC-1α. Cardiovasc Res 79:208–217
Riehle C, Wende AR, Zaha VG et al (2011) PGC-1beta deficiency accelerates the transition to heart failure in pressure overload hypertrophy. Cir Res 109:783–793
Bugger H et al (2010) Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res 85:376–384
Ide T et al (2001) Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 88:529–535
Garnier A et al (2003) Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol 551:491–501
Scheubel RJ et al (2002) Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol 40:2174–2181
Sebastiani M et al (2007) Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J Am Coll Cardiol 50:1362–1369
Karamanlidis G et al (2010) Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res 106:1541–1548
Suematsu N et al (2003) Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107:1418–1423
Tsutsui H, Ide T, Kinugawa S (2006) Mitochondrial oxidative stress, DNA damage, and heart failure. Antioxid Redox Signal 8:1737–1744
Matsushima S et al (2006) Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 113:1779–1786
Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88:611–638
Rocher C et al (2008) Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases. J Bioenerg Biomembr 40:59–67
Ikeuchi M et al (2005) Overexpression of mitochondrial transcription factor ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 112:683–690
Tsutsui H, Kinugawa S, Matsushima S (2009) Mitochondrial oxidative stress and dysfunction in myocardial remodeling. Cardiovasc Res 81:449–456
Dolezal P, Likic V, Tachezy J, Lithgow T (2006) Evolution of the molecular machines for protein import into mitochondria. Science 313:314–318
Baker MJ, Frazier AE, Gulbis JM, Ryan MT (2007) Mitochondrial protein-import machinery: correlating structure with function. Trends Cell Biol 17:456–464
Mac Kenzie JA, Payne RM (2007) Mitochondrial protein import and human health and disease. Biochim Biophys Acta 1772:509–523
Dabkowski ER et al (2010) Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially-distinct mitochondrial proteomes. Am J Physiol Heart Circ Physiol 299:H529–H540
Hatch GM (2004) Cell biology of cardiac mitochondrial phospholipids. Biochem Cell Biol 82:99–112
Chicco AJ, Sparagna GC (2006) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292:C33–C44
Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65:2493–2506
Athea Y et al (2007) AMP-activated protein kinase {alpha} 2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function. Diabetes 56:786–794
Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription co-activators. Cell Metab 1:361–370
Wang P et al (2010) Peroxisome proliferator-activated receptor delta is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart. Circ Res 106:911–919
Hock MB, Kralli A (2009) Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 71:177–203
Huss JM, Torra IP, Staels B, Giguere V, Kelly DP (2004) Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24:9079–9091
Lai L et al (2008) Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 22:1948–1961
Garnier A et al (2005) Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle. FASEB J 19:43–52
Soriano FX et al (2006) Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55:1783–1791
Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22:79–99
Ong SB et al (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022
Joubert F et al (2008) Local energetic regulation of sarcoplasmic and myosin ATPase is differently impaired in rats with heart failure. J Physiol 586:5181–5192
Witt H et al (2008) Sex-specific pathways in early cardiac response to pressure overload in mice. J Mol Med 86:1013–1024
Watson PA et al (2007) Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise. Am J Physiol Heart Circ Physiol 293:H246–H259
Faerber G et al (2011) Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor gamma co-activator levels and mitochondrial dysfunction. J Thorac Cardiovasc Surg 141:492–500
Garnier A et al (2009) Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II. Circ Heart Fail 2:342–350
Sihag S, Cresci S, Li AY, Sucharov CC, Lehman JJ (2008) PGC-1alpha and ERRalpha target gene down regulation is a signature of the failing human heart. J Mol Cell Cardiol 46:201–212
Huss JM et al (2007) The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab 6:25–37
Ventura-Clapier R, Kuznetsov A, Veksler V, Boehm E, Anflous K (1998) Functional coupling of creatine kinases in muscles: species and tissue specificity. Mol Cell Biochem 184:231–247
Arany Z et al (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271
Lehman JJ et al (2008) The transcriptional coactivator PGC-1alpha is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. Am J Physiol Heart Circ Physiol 295:H185–H196
Dufour CR et al (2007) Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma. Cell Metab 5:345–356
Twig G et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446
Saito T, Sadoshima J (2015) Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart. Circ Res 116:1477–1490
Knowlton AA, Liu TT (2016) Mitochondrial dynamics and heart failure. Compr Physiol 6:507–526
Saks VA et al (2001) Intracellular energetic units in red muscle cells. Biochem J 356:643–657
Saks V et al (2006) Cardiac system bioenergetics: metabolic basis of Frank-Starling law. J Physiol 571:253–273
Guzun R, Saks V (2010) Application of the principles of systems biology and Wiener’s cybernetics for analysis of regulation of energy fluxes in muscle cells in vivo. Int J Mol Sci 11:982–1019
Shimizu J, Todaka K, Burkhoff D (2002) Load dependence of ventricular performance explained by model of calcium-myofilament interactions. Am J Physiol Heart Circ Physiol 282:H1081–H1091
Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34:1259–1271
Weiss JN, Korge P (2001) The cytoplasm: no longer a well-mixed bag. Circ Res 89:108–110
Weiss J, Hiltbrand B (1985) Functional compartmentation of glycolytic versus oxidative metabolism in isolated rabbit heart. J Clin Invest 75:436–447
Saks VA et al (2004) Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism. Mol Cell Biochem 256–257:185–199
Rostovtseva TK et al (2008) Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci U S A 105:18746–18751
Kay L et al (1997) Study of regulation of mitochondrial respiration in vivo, an analysis of influence of ADP diffusion and possible role of cytoskeleton. Biochim Biophys Acta 1322:41–59
Gong G et al (2003) Oxidative capacity in failing hearts. Am J Phys 285:H541–H548
Jarreta D et al (2000) Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Cardiovasc Res 45:860–865
Marin-Garcia J, Goldenthal MJ, Moe GW (2001) Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc Res 52:103–110
Liu J et al (2001) Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol Heart Circ Physiol 281:H1319–H1326
Cieniewski-Bernard C et al (2008) Proteomic analysis of left ventricular remodeling in an experimental model of heart failure. J Proteome Res 7:5004–5016
Gao Z et al (2008) Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. Physiol Genomics 35:222–230
Gao Z et al (2006) Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure. J Mol Cell Cardiol 40:76–86
Murray AJ et al (2008) Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol 44:694–700
Lisa FD, Bernardi P (2009) A CaPful of mechanisms regulating the mitochondrial permeability transition. J Mol Cell Cardiol 46:775–780
Marcil M et al (2006) Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress. J Mol Cell Cardiol 41:998–1009
Sousa ED et al (2002) Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity. Cardiovasc Res 56:260–268
Boudina S et al (2002) Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart. Am J Physiol Heart Circ Physiol 282:H821–H831
Zoll J et al (2006) ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction. J Appl Physiol 101:385–391
Belmadani S, Pous C, Ventura-Clapier R, Fischmeister R, Mery PF (2002) Post-translational modifications of cardiac tubulin during chronic heart failure in the rat. Mol Cell Biochem 237:39–46
Akki A, Gupta A, Weiss RG (2013) Magnetic resonance imaging and spectroscopy of the murine cardiovascular system. Am J Physiol Heart Circ Physiol 304(5):H633–H648
Chacko VP, Aresta F, Chacko SM, Weiss RG (2000) MRI/MRS assessment of in vivo murine cardiac metabolism, morphology, and function at physiological heart rates. Am J Physiol Heart Circ Physiol 279(5):H2218–H2224
Gupta A, Chacko VP, Schär M, Akki A, Weiss RG (2011) Impaired ATP kinetics in failing in vivo mouse heart. Circ Cardiovasc Imaging 4(1):42–50
Gupta A et al (2012) Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J Clin Invest 122(1):291–302
Gupta A, Chacko VP, Weiss RG (2009) Abnormal energetics and ATP depletion in pressure-overload mouse hearts: in vivo high-energy phosphate concentration measures by noninvasive magnetic resonance. Am J Physiol Heart Circ Physiol 297:H59–H64
Gupta A et al (2013) Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One 8(10):e74675
Akki A et al (2012) Creatine kinase over-expression improves ATP kinetics and contractile function in post-ischemic myocardium. Am J Physiol Heart Circ Physiol 303:H844–H852
Neubauer S et al (1995) Impairment of energy metabolism inintact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest 95:1092–1100
Ye Y, Gong G, Ochiai K, Liu J, Zhang J (2001) High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation 103:1570–1576
Weiss RG, Gerstenblith G, Bottomley PA (2005) ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A 102(3):808–813
Smith CS, Bottomley PA, Schulman SP, Gerstenblith G, Weiss RG (2006) Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation 114(11):1151–1158
Hardy CJ, Weiss RG, Bottomley PA, Gerstenblith G (1991) Altered myocardial high energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 122:795–801
Conway MA et al (1991) Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by P-31 magnetic resonance spectroscopy. Lancet 338:973–976
Neubauer S et al (1992) 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary heart disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86:1810–1818
Ingwall JS (2009) Energy metabolism in heart failure and remodeling. Cardiovasc Res 81:412–419
Beer M et al (2002) Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol 40:1267–1274
Neubauer S et al (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96:2190–2196
Crilley JG et al (2003) Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol 41:1776–1782
Tian R, Nascimben L, Ingwall JS, Lorell BH (1997) Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 96:1313–1319
Bessman SP, Geiger PJ (1981) Transport of energy in muscle: the phosphoryl creatine shuttle. Science 211:448–452
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands—the phosphocreatine circuit for cellular energy homeostasis. Biochem J 281:21–40
Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206:2039–2047
Akki A et al (2014) Skeletal muscle ATP kinetics are impaired in frail mice. Age 36:21–30
Wyss M, Smeitink J, Wevers RA, Wallimann T (1992) Mitochondrial creatine kinase—a key enzyme of aerobic energy metabolism. Biochim Biophys Acta 1102:119–166
Ventura-Clapier R, Veksler V, Hoerter JA (1994) Myofibrillar creatine kinase and cardiac contraction. Mol Cell Biochem 133:125–144
Saks V et al (2010) Structure-function relationships in feedback regulation of energy fluxes in vivo in health and disease: mitochondrial interactosome. Biochim Biophys Acta 1797:678–697
Joubert F, Hoerter JA, Mazet JL (2002) Modeling the energy transfer pathways. Creatine kinase activities and heterogeneous distribution of ADP in the perfused heart. Mol Biol Rep 29:177–182
Joubert F, Mazet JL, Mateo P, Hoerter JA (2002) 31P NMR detection of subcellular creatine kinase fluxes in the perfused rat heart: contractility modifies energy transfer pathways. J Biol Chem 277:18469–18476
Ingwall JS, Atkinson DE, Clarke K, Fetters JK (1990) Energetic correlates of cardiac failure: changes in the creatine kinase system in the failing myocardium. Eur Heart J 11:108–115
Sylven C, Lin L, Kallner A, Sotonyi P, Somogyi E, Jansson E (1991) Dynamics of creatine kinase shuttle enzymes in the human heart. Eur J Clin Investig 21:350–354
Hove MT, Neubauer S (2007) MR spectroscopy in heart failure—clinical and experimental findings. Heart Fail Rev 12:48–57
Joubert F, Gillet B, Mazet JL, Mateo P, Beloeil J, Hoerter JA (2000) Evidence for myocardial ATP compartmentation from NMR inversion transfer analysis of creatine kinase fluxes. Biophys J 79:1–13
van der Vusse GJ, van Bilsen M, Glatz JF (2000) Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res 45:279–293
Glatz JF, Luiken JJ, Bonen A (2001) Involvement of membrane-associated proteins in the acute regulation of cellular fatty acid uptake. J Mol Neurosci 16:123–132
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258
Banke NH et al (2010) Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha. Circ Res 107:233–241
Koves TR et al (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56
Cook GA et al (2001) Differential regulation of carnitine palmitoyltransferase-I gene isoforms (CPT-I alpha and CPT-I beta) in the rat heart. J Mol Cell Cardiol 33:317–329
Sorokina N et al (2007) Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation 115:2033–2041
Zammit VA, Fraser F, Orstorphine CG (1997) Regulation of mitochondrial outermembrane carnitine palmitoyltransferase (CPT I): role of membrane-topology. Adv Enzym Regul 37:295–317
Hamilton C, Saggerson ED (2000) Malonyl-CoA metabolism in cardiac myocytes. Biochem J 350(pt 1):61–67
Dyck JR et al (2006) Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114:1721–1728
Zhou L et al (2008) Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol 294:H954–H960
Kato T et al (2010) Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail 3:420–430
Doenst T et al (2010) Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 86:461–470
Rosenblatt-Velin N, Montessuit C, Papageorgiou I, Terrand J, Lerch R (2001) Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism. Cardiovasc Res 52:407–416
Heather LC et al (2006) Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res 72:430–437
Akki A, Smith K, Seymour AM (2008) Compensated cardiac hypertrophy is characterised by a decline in palmitate oxidation. Mol Cell Biochem 311:215–224
Allard MF, Schönekess BO, Henning SL, English DR, Lopaschuk GD (1994) Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Phys 267:H742–H750
Christe ME, Rodgers RL (1994) Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol 26:1371–1375
Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP (1996) Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94:2837–2842
Aerni-Flessner L, Abi-Jaoude M, Koenig A, Payne M, Hruz PW (2012) GLUT4, GLUT1, and GLUT8 are the dominant GLUT transcripts expressed in the murine left ventricle. Cardiovasc Diabetol 11:63
Abel ED (2004) Glucose transport in the heart. Front Biosci 9:201–215
Entman ML, Bornet EP, Van Winkle WB, Goldstein MA, Schwartz A (1977) Association of glycogenolysis with cardiac sarcoplasmic reticulum, II: effect of glycogen depletion, deoxycholate solubilization and cardiac ischemia: evidence for a phorphorylase kinase membrane complex. J Mol Cell Cardiol 9:515–528
Kusuoka H, Marban E (1994) Mechanism of the diastolic dysfunction induced by glycolytic inhibition. Does adenosine triphosphate derived from glycolysis play a favored role in cellular Ca2+ homeostasis in ferret myocardium? J Clin Invest 93:1216–1223
Des Rosiers C, Labarthe F, Lloyd SG, Chatham JC (2011) Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res 90:210–219
Russell RR 3rd, Taegtmeyer H (1991) Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate. J Clin Invest 87:384–390
Zhabyeyev P et al (2013) Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc Res 97:676–685
Amorim PA et al (2010) Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression. J Thorac Cardiovasc Surg 140:1160–1167
Degens H et al (2006) Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart. Basic Res Cardiol 101:17–26
Dai DF et al (2012) Mitochondrial proteome remodeling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 93:79–88
Dodd MS et al (2012) In vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart. Cardiovasc Res 95:69–76
Dávila-Román VG et al (2002) Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 40:271–277
Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients: the heart outcomes prevention evaluation study investigators. N Engl J Med 342:154–160
Lonn E et al (2005) HOPE and HOPE-TOO trial investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293:1338–1347
Dai DF et al (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108:837–846
Dai DF et al (2011) Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 58:73–82
Burgoyne JR, Mongue-Din H, Eaton P, Shah AM (2012) Redox signaling in cardiac physiology and pathology. Circ Res 111:1091–1106
Schönfeld P, Wojtczak L (2007) Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport. Biochim Biophys Acta 1767:1032–1040
Opie LH, Knuuti J (2009) The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol 54:1637–1646
Krishnan J et al (2009) Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 9:512–524
Gupte SA et al (2006) Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart. J Mol Cell Cardiol 41:340–349
Hecker PA et al (2013) Glucose 6-phosphate dehydrogenase deficiency increases redox stress and moderately accelerates the development of heart failure. Circ Heart Fail 6:118–126
Du XL et al (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97:12222–12226
Facundo HT et al (2012) O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy. Am J Physiol Heart Circ Physiol 302:H2122–H2130
Wilkins BJ et al (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118
Watson LJ et al (2010) O-linked β-N-acetylglucosamine transferase is indispensable in the failing heart. Proc Natl Acad Sci U S A 107:17797–17802
Heling A et al (2000) Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ Res 86:846–853
Schneider AG, Sultan KR, Pette D (1999) Muscle LIM protein: expressed in slow muscle and induced in fast muscle by enhanced contractile activity. Am J Phys 276:C900–C906
Veksler VI et al (1995) Muscle creatine kinase-deficient mice. II. Cardiac and skeletal muscles exhibit tissue-specific adaptation of the mitochondrial function. J Biol Chem 270:19921–19929
Appaix F et al (2003) Possible role of cytoskeleton in intracellular arrangement and regulation of mitochondria. Exp Physiol 88:175–190
Kaasik A et al (2001) Energetic crosstalk between organelles: architectural integration of energy production and utilization. Circ Res 89:153–159
Mekhfi H et al (1990) Myocardial adaptation to creatine deficiency in rats fed with beta-guanidino propionic acid, a creatine analogue. Am J Phys 258:H1151–H1158
Arber S et al (1997) MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88:393–403
Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000) Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 150:1283–1297
Boehm E, Ventura-Clapier R, Mateo P, Lechene P, Veksler V (2000) Glycolysis supports calcium uptake by the sarcoplasmic reticulum in skinned ventricular fibers of mice deficient in mitochondrial and cytosolic creatine kinase. J Mol Cell Cardiol 32:891–902
Saks V et al (2003) Heterogeneity of ADP diffusion and regulation of respiration in cardiac cells. Biophys J 84:3436–3456
Gupta A, Gupta S, Young D, Das B, McMahon J, Sen S (2010) Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure. Lab Investig 90:520–530
Hein S, Kostin S, Heling A, Maeno Y, Schaper J (2000) The role of the cytoskeleton in heart failure. Cardiovasc Res 45:273–278
Cooper G (2006) Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction. Am J Physiol Heart Circ Physiol 291:H1003–H1014
van den Bosch BJ et al (2005) Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice. Cardiovasc Res 65:411–418
Schaper J et al (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83:504–514
Sabbah HN et al (1992) Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 24:1333–1347
Chen L, Knowlton AA (2010) Mitochondria and heart failure: new insights into an energetic problem. Minerva Cardioangiol 58:213–229
van Bilsen M, van Nieuwenhoven FA, van der Vusse GJ (2008) Metabolic remodeling of the failing heart: beneficial or detrimental? Cardiovasc Res 81:420–428
Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547–555
Mori J et al (2012) Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ Heart Fail 5:493–503
Pellieux C et al (2006) Overexpression of angiotensinogen in the myocardium induces downregulation of the fatty acid oxidation pathway. J Mol Cell Cardiol 41:459–466
Pellieux C, Montessuit C, Papageorgiou I, Lerch R (2009) Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-alpha. Cardiovasc Res 82:341–350
Fillmore N, Mori J, Lopaschuk GD (2014) Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 171:2080–2090
Vermes E et al (2003) Studies of left ventricular dysfunction. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the studies of left ventricular dysfunction (SOLVD). Circulation 107:1291–1296
Yusuf S et al (2005) Candesartan in heart failure-assessment of reduction in mortality and morbidity program investigators. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 112:48–53 2005. Erratum in: Circulation 112: e292
Wallhaus TR, Taylor M, De Grado TR, Russell DC (2001) Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 103:2441–2446
Spoladore R et al (2013) Beneficial effects of beta-blockers on left ventricular function and cellular energy reserve in patients with heart failure. Fundam Clin Pharmacol 27:455–464
Christenson SD et al (2008) Effects of simultaneous and optimized sequential cardiac resynchronization therapy on myocardial oxidative metabolism and efficiency. J Cardiovasc Electrophysiol 19:125–132
Kitaizumi K et al (2008) Positron emission tomographic demonstration of myocardial oxidative metabolism a case of left ventricular restoration after cardiac resynchronization therapy. Circ J 72:1900–1903
Agnetti G et al (2010) Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dys-synchronous failing hearts. Circ Cardiovasc Genet 3:78–87
Sajgalik P et al (2016) Current status of left ventricular assist device therapy. Mayo Clin Proc 91(7):927–940
de Brouwer KF et al (2006) Specific and sustained down-regulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice. J Mol Cell Cardiol 40:838–845
Lionetti V, Stanley WC, Recchia FA (2011) Modulating fatty acid oxidation in heart failure. Cardiovac Res 90:202–209
Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451:919–928
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Gupta, A., Houston, B. A comprehensive review of the bioenergetics of fatty acid and glucose metabolism in the healthy and failing heart in nondiabetic condition. Heart Fail Rev 22, 825–842 (2017). https://doi.org/10.1007/s10741-017-9623-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-017-9623-6