Metabolic coordination of physiological and pathological cardiac remodeling

Circulation Research

Volumn 123, Issue 1, 2018, Pages 107-128

  Gibb, Andrew A ^a   Hill, Bradford G ^b  

^a TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b University of Louisville School of Medicine   (United States)

Author keywords

Exercise; Glucose; Heart failure; Hypertrophy; Mitochondria; Pregnancy; Systems biology

Indexed keywords

ADENOSINE TRIPHOSPHATE; FIBROBLAST GROWTH FACTOR 21; GLUCOSE; MITOFUSIN 1; MITOFUSIN 2; PROTEIN KINASE B;

ATRIAL FIBRILLATION; CONCEPTUAL FRAMEWORK; COORDINATION; ENZYME ACTIVITY; EXERCISE; GENE EXPRESSION; GLUCOSE METABOLISM; GLUCOSE OXIDATION; GLUCOSE TRANSPORT; HEART; HEART DEVELOPMENT; HEART FUNCTION; HEART HYPERTROPHY; HEART INFARCTION; HEART MUSCLE METABOLISM; HEART STROKE VOLUME; HEART VENTRICLE FIBRILLATION; HEART VENTRICLE REMODELING; HOMEOSTASIS; HUMAN; OXIDATION REDUCTION STATE; PHENOTYPE; PREGNANCY; PRIORITY JOURNAL; REPERFUSION INJURY; REVIEW; ADAPTATION; BIOSYNTHESIS; CARDIAC MUSCLE; CARDIOMEGALY; DIABETES MELLITUS; ENERGY METABOLISM; EXERCISE INDUCED CARDIOMEGALY; FEMALE; FETUS HEART; GROWTH, DEVELOPMENT AND AGING; HEART FAILURE; METABOLISM; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ADAPTATION, PHYSIOLOGICAL; ADENOSINE TRIPHOSPHATE; CARDIOMEGALY; CARDIOMEGALY, EXERCISE-INDUCED; DIABETES MELLITUS; ENERGY METABOLISM; EXERCISE; FEMALE; FETAL HEART; GENE EXPRESSION; GLUCOSE; HEART; HEART FAILURE; HUMANS; MYOCARDIUM; PREGNANCY; SIGNAL TRANSDUCTION; VENTRICULAR REMODELING;

EID: 85053842783     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.118.312017     Document Type: Review

References (359)

1. Taegtmeyer H, Lam T, Davogustto G. Cardiac metabolism in perspective. Compr Physiol. 2016;6:1675-1699. doi: 10.1002/cphy.c150056.
2. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013;113:709-724.
3. Opie LH. Metabolism of the heart in health and disease. II. Am Heart J. 1969;77:100-122 contd.
4. Opie LH. Heart Physiology: From Cell to Circulation. Philadelphia, PA: Lippincott Williams & Wilkins. 2004:308-354.
5. Schönekess BO. Competition between lactate and fatty acids as sources of ATP in the isolated working rat heart. J Mol Cell Cardiol. 1997;29:2725-2733. doi: 10.1006/jmcc.1997.0504.
6. Kaijser L, Berglund B. Myocardial lactate extraction and release at rest and during heavy exercise in healthy men. Acta Physiol Scand. 1992;144:39-45. doi: 10.1111/j.1748-1716.1992.tb09265.x.
7. Bertrand ME, Carre AG, Ginestet AP, Lefebvre JM, Desplanque LA, Lekieffre J P. Maximal exercise in normal subjects: changes in coronary sinus blood fow, contractility and myocardial extraction of FFA and lactate. Eur J Cardiol. 1977;5:481-491.
8. Drake AJ, Haines JR, Noble MI. Preferential uptake of lactate by the normal myocardium in dogs. Cardiovasc Res. 1980;14:65-72.
9. Keul J. Myocardial metabolism in athletes. Adv Exp Med Biol. 1971;11:447-467.
10. Williamson JR, Krebs HA. Acetoacetate as fuel of respiration in the perfused rat heart. Biochem J. 1961;80:540-547.
11. Hall LM. Preferential oxidation of acetoacetate by the perfused heart. Biochem Biophys Res Commun. 1961;6:177-179.
12. Barnes RH, Mackay EM, Moe GK, Vissscher MB. The utilization of beta-hydroxybutyric acid by the isolated mammalian heart and lungs. Am J Physiol. 1938;123:272-279.
13. Little JR, Goto M, Spitzer JJ. Effect of ketones on metabolism of FFA by dog myocardium and skeletal muscle in vivo. Am J Physiol. 1970;219:1458-1463. doi: 10.1152/ajplegacy.1970.219.5.1458.
14. Lopaschuk GD, Saddik M. The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischemia. Mol Cell Biochem. 1992;116:111-116.
15. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schönekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994;1213:263-276.
16. Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev. 2002;7:115-130.
17. Goodwin GW, Ahmad F, Doenst T, Taegtmeyer H. Energy provision from glycogen, glucose, and fatty acids on adrenergic stimulation of isolated working rat hearts. Am J Physiol. 1998;274:H1239-H1247.
18. Taegtmeyer H. Carbohydrate interconversions and energy production. Circulation. 1985;72:IV1-IV8.
19. Taegtmeyer H, Young ME, Lopaschuk GD, et al; American Heart Association Council on Basic Cardiovascular Sciences. Assessing cardiac metabolism: a scientifc statement from the American Heart Association. Circ Res. 2016;118:1659-1701. doi: 10.1161/RES.0000000000000097.
20. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-258. doi: 10.1152/physrev.00015.2009.
21. Lopaschuk GD. Metabolic modulators in heart disease: past, present, and future. Can J Cardiol. 2017;33:838-849. doi: 10.1016/j.cjca. 2016.12.013.
22. Goodwin GW, Taegtmeyer H. Improved energy homeostasis of the heart in the metabolic state of exercise. Am J Physiol Heart Circ Physiol. 2000;279:H1490-H1501. doi: 10.1152/ajpheart.2000.279.4.H1490.
23. Allard MF, Schönekess BO, Henning SL, English DR, Lopaschuk GD. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol. 1994;267:H742-H750. doi: 10.1152/ajpheart.1994.267.2.H742.
24. Ichihara K, Neely JR, Siehl DL, Morgan HE. Utilization of leu-cine by working rat heart. Am J Physiol. 1980;239:E430-E436. doi: 10.1152/ajpendo.1980.239.6.E430.
25. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing sub-strates in the isolated working rat heart. Biochem J. 1980;186:701-711.
26. Bian F, Kasumov T, Thomas KR, Jobbins KA, David F, Minkler PE, Hoppel CL, Brunengraber H. Peroxisomal and mitochondrial oxidation of fatty acids in the heart, assessed from the 13C labeling of malonyl-CoA and the acetyl moiety of citrate. J Biol Chem. 2005;280:9265-9271. doi: 10.1074/jbc.M412850200.
27. Cohen DM, Guthrie PH, Gao X, Sakai R, Taegtmeyer H. Glutamine cycling in isolated working rat heart. Am J Physiol Endocrinol Metab. 2003;285:E1312-E1316. doi: 10.1152/ajpendo.00539.2002.
28. Chatham JC, Young ME. Regulation of myocardial metabolism by the car-diomyocyte circadian clock. J Mol Cell Cardiol. 2013;55:139-146. doi: 10.1016/j.yjmcc.2012.06.016.
29. Young ME. Temporal partitioning of cardiac metabolism by the car-diomyocyte circadian clock. Exp Physiol. 2016;101:1035-1039. doi: 10.1113/EP085779.
30. Martino TA, Young ME. Infuence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. J Biol Rhythms. 2015;30:183-205. doi: 10.1177/0748730415575246.
31. Henschen S. Skidlauf und Skidwettlauf. Eine medizinische Sportstudie. Mitt Med Klin Upsala. Jena. Fischer Verlag. 1899;2:15.
32. Darling EA. The effects of training. A study of the Harvard University crews. Boston Med Surg J. 1899;CXLI:229-233.
33. Beckner GL, Winsor T. Cardiovascular adaptations to prolonged physical effort. Circulation. 1954;9:835-846.
34. Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol. 2013;14:38-48. doi: 10.1038/nrm3495.
35. DeMaria AN, Neumann A, Lee G, Fowler W, Mason DT. Alterations in ventricular mass and performance induced by exercise training in man evaluated by echocardiography. Circulation. 1978;57:237-244.
36. Pluim BM, Lamb HJ, Kayser HW, Leujes F, Beyerbacht HP, Zwinderman AH, van der Laarse A, Vliegen HW, de Roos A, van der Wall EE. Functional and metabolic evaluation of the athlete's heart by magnetic resonance imaging and dobutamine stress magnetic resonance spectros-copy. Circulation. 1998;97:666-672.
37. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The ath-lete's heart. A meta-analysis of cardiac structure and function. Circulation. 2000;101:336-344.
38. Burelle Y, Wambolt RB, Grist M, Parsons HL, Chow JC, Antler C, Bonen A, Keller A, Dunaway GA, Popov KM, Hochachka PW, Allard MF. Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2004;287:H1055-H1063. doi: 10.1152/ajpheart.00925.2003.
39. Calvert JW, Condit ME, Aragón JP, Nicholson CK, Moody BF, Hood RL, Sindler AL, Gundewar S, Seals DR, Barouch LA, Lefer DJ. Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ Res. 2011;108:1448-1458. doi: 10.1161/CIRCRESAHA.111.241117.
40. Platt C, Houstis N, Rosenzweig A. Using exercise to measure and modify cardiac function. Cell Metab. 2015;21:227-236. doi: 10.1016/j.cmet.2015.01.014.
41. Wilson M, O'Hanlon R, Prasad S, Deighan A, Macmillan P, Oxborough D, Godfrey R, Smith G, Maceira A, Sharma S, George K, Whyte G. Diverse patterns of myocardial fbrosis in lifelong, veteran endurance athletes. J Appl Physiol (1985). 2011;110:1622-1626. doi: 10.1152/japplphysiol.01280.2010.
42. La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, Bogaert J, Macisaac AI, Heidbüchel H, Prior DL. Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. Eur Heart J. 2012;33:998-1006. doi: 10.1093/eurheartj/ehr397.
43. O'Keefe JH, Patil HR, Lavie CJ, Magalski A, Vogel RA, McCullough PA. Potential adverse cardiovascular effects from excessive endurance exer-cise. Mayo Clin Proc. 2012;87:587-595.
44. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial f-brillation in vigorously exercising middle aged men: case-control study. BMJ. 1998;316:1784-1785.
45. Vega RB, Konhilas JP, Kelly DP, Leinwand LA. Molecular mechanisms underlying cardiac adaptation to exercise. Cell Metab. 2017;25:1012-1026. doi: 10.1016/j.cmet.2017.04.025.
46. Hawley JA, Hargreaves M, Joyner MJ, Zierath JR. Integrative biology of exercise. Cell. 2014;159:738-749. doi: 10.1016/j.cell.2014. 10.029.
47. Egan B, Zierath JR. Exercise metabolism and the molecular regula-tion of skeletal muscle adaptation. Cell Metab. 2013;17:162-184. doi: 10.1016/j.cmet.2012.12.012.
48. Khouri EM, Gregg DE, Rayford CR. Effect of exercise on cardiac output, left coronary fow and myocardial metabolism in the unanesthetized dog. Circ Res. 1965;17:427-437.
49. Olver TD, Ferguson BS, Laughlin MH. Molecular mechanisms for ex-ercise training-induced changes in vascular structure and function: skeletal muscle, cardiac muscle, and the brain. Prog Mol Biol Transl Sci. 2015;135:227-257. doi: 10.1016/bs.pmbts.2015.07.017.
50. Mootha VK, Arai AE, Balaban RS. Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol. 1997;272:H769-H775. doi: 10.1152/ajpheart.1997.272.2.H769.
51. Goodwin GW, Taylor CS, Taegtmeyer H. Regulation of energy metabolism of the heart during acute increase in heart work. J Biol Chem. 1998;273:29530-29539.
52. Neely JR, Bowman RH, Morgan HE. Effects of ventricular pressure devel-opment and palmitate on glucose transport. Am J Physiol. 1969;216:804-811. doi: 10.1152/ajplegacy.1969.216.4.804.
53. Crass MF III, McCaskill ES, Shipp JC. Effect of pressure development on glucose and palmitate metabolism in perfused heart. Am J Physiol. 1969;216:1569-1576. doi: 10.1152/ajplegacy.1969.216.6.1569.
54. Opie LH, Mansford KR, Owen P. Effects of increased heart work on gly-colysis and adenine nucleotides in the perfused heart of normal and dia-betic rats. Biochem J. 1971;124:475-490.
55. Zhou L, Huang H, Yuan CL, Keung W, Lopaschuk GD, Stanley WC. Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical effciency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2008;294:H954-H960. doi: 10.1152/ajpheart.00557.2007.
56. Bergman BC, Tsvetkova T, Lowes B, Wolfel EE. Myocardial FFA me-tabolism during rest and atrial pacing in humans. Am J Physiol Endocrinol Metab. 2009;296:E358-E366. doi: 10.1152/ajpendo.90747.2008.
57. Bergman BC, Tsvetkova T, Lowes B, Wolfel EE. Myocardial glucose and lactate metabolism during rest and atrial pacing in humans. J Physiol. 2009;587:2087-2099. doi: 10.1113/jphysiol.2008.168286.
58. Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol. 1974;36:413-459. doi: 10.1146/annurev.ph.36.030174.002213.
59. Crass MF III, Shipp JC, Pieper GM. Effects of catecholamines on myocar-dial endogenous substrates and contractility. Am J Physiol. 1975;228:618-627. doi: 10.1152/ajplegacy.1975.228.2.618.
60. Gousios A, Felts JM, Havel RJ. Effect of catecholamines, glucose, insulin, and changes of fow on the metabolism of free fatty acids by the myocardium. Metabolism. 1965;14:826-831.
61. Buse MG, Biggers JF, Drier C, Buse JF. The effect of epinephrine, glu-cagon, and the nutritional state on the oxidation of branched chain amino acids and pyruvate by isolated hearts and diaphragms of the rat. J Biol Chem. 1973;248:697-706.
62. Collins-Nakai RL, Noseworthy D, Lopaschuk GD. Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism. Am J Physiol. 1994;267:H1862-H1871. doi: 10.1152/ajpheart.1994.267.5.H1862.
63. Williamson JR. Metabolic effects of epinephrine in the isolated, perfused rat heart. I. Dissociation of the glycogenolytic from the metabolic stimulatory effect. J Biol Chem. 1964;239:2721-2729.
64. Clark MG, Patten GS. Epinephrine activation of phosphofructokinase in perfused rat heart independent of changes in effector concentrations. J Biol Chem. 1981;256:27-30.
65. Clark MG, Patten GS. Adrenaline activation of phosphofructokinase in rat heart mediated by alpha-receptor mechanism independent of cyclic AMP. Nature. 1981;292:461-463.
66. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest. 1988;82:2017-2025. doi: 10.1172/JCI113822.
67. Kemppainen J, Fujimoto T, Kalliokoski KK, Viljanen T, Nuutila P, Knuuti J. Myocardial and skeletal muscle glucose uptake during exercise in humans. J Physiol. 2002;542:403-412.
68. Lassers BW, Kaijser L, Wahlqvist M, Carlson LA. Effect of prolonged exercise on myocardial metabolism in man. Br Heart J. 1971;33:609.
69. Takala TE, Ruskoaho HJ, Hassinen IE. Transmural distribution of cardiac glucose uptake in rat during physical exercise. Am J Physiol. 1983;244:H131-H137. doi: 10.1152/ajpheart.1983.244.1.H131.
70. Rodahl K, Miller HI, Issekutz B Jr. Plasma free fatty acids in exercise. J Appl Physiol. 1964;19:489-492. doi: 10.1152/jappl.1964. 19.3.489.
71. Lassers BW, Wahlqvist ML, Kaijser L, Carlson LA. Effect of nicotinic acid on myocardial metabolism in man at rest and during exercise. J Appl Physiol. 1972;33:72-80. doi: 10.1152/jappl.1972.33.1.72.
72. Lassers BW, Kaijser L, Carlson LA. Myocardial lipid and carbohydrate metabolism in healthy, fasting men at rest: studies during continuous infu-sion of 3 H-palmitate. Eur J Clin Invest. 1972;2:348-358.
73. Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J Clin Invest. 1987;79:359-366. doi: 10.1172/JCI112820.
74. Gertz EW, Wisneski JA, Neese R, Bristow JD, Searle GL, Hanlon JT. Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation. 1981;63:1273-1279.
75. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Craig JC. Dual carbon-labeled isotope experiments using D-[6-14C] glucose and L-[1, 2, 3-13C3] lactate: a new approach for investigating human myocardial metabolism during ischemia. J Am Coll Cardiol. 1985;5:1138-1146.
76. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Morris DL, Craig JC. Metabolic fate of extracted glucose in normal human myocardium. J Clin Invest. 1985;76:1819-1827. doi: 10.1172/JCI112174.
77. Coyle EF. Physical activity as a metabolic stressor. Am J Clin Nutr. 2000;72:512S-520S. doi: 10.1093/ajcn/72.2.512S.
78. Coggan AR. Plasma glucose metabolism during exercise in humans. Sports Med. 1991;11:102-124.
79. Riehle C, Wende AR, Zhu Y et al. Insulin receptor substrates are essen-tial for the bioenergetic and hypertrophic response of the heart to exercise training. Mol Cell Biol. 2014;34:3450-3460.
80. Gibb AA, Epstein PN, Uchida S, Zheng Y, McNally LA, Obal D, Katragadda K, Trainor P, Conklin DJ, Brittian KR, Tseng MT, Wang J, Jones SP, Bhatnagar A, Hill BG. Exercise-induced changes in glucose metabolism promote physiological cardiac growth. Circulation. 2017;136:2144-2157. doi: 10.1161/CIRCULATIONAHA. 117.028274.
81. Hafstad AD, Boardman NT, Lund J, Hagve M, Khalid AM, Wisløff U, Larsen TS, Aasum E. High intensity interval training alters substrate utilization and reduces oxygen consumption in the heart. J Appl Physiol (1985). 2011;111:1235-1241. doi: 10.1152/japplphysiol.00594.2011.
82. Lai L, Leone TC, Keller MP, Martin OJ, Broman AT, Nigro J, Kapoor K, Koves TR, Stevens R, Ilkayeva OR, Vega RB, Attie AD, Muoio DM, Kelly DP. Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ Heart Fail. 2014;7:1022-1031. doi: 10.1161/CIRCHEARTFAILURE.114.001469.
83. Papadopoulos NM, Bloor CM, Standefer JC. Effects of exercise and training on plasma lipids and lipoproteins in the rat. J Appl Physiol. 1969;26:760-763. doi: 10.1152/jappl.1969.26.6.760.
84. Monleon D, Garcia-Valles R, Morales JM, Brioche T, Olaso-Gonzalez G, Lopez-Grueso R, Gomez-Cabrera MC, Viña J. Metabolomic analysis of long-term spontaneous exercise in mice suggests increased li-polysis and altered glucose metabolism when animals are at rest. J Appl Physiol (1985). 2014;117:1110-1119. doi: 10.1152/japplphysiol. 00585.2014.
85. Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED. Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol. 2008;22:2531-2543.
86. Cai MX, Shi XC, Chen T, Tan ZN, Lin QQ, Du SJ, Tian ZJ. Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model. Life Sci. 2016;149:1-9. doi: 10.1016/j.lfs.2016.02.055.
87. Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur Heart J. 2014;35:2722-2731. doi: 10.1093/eurheartj/ehs338.
88. Pozuelo Rubio M, Peggie M, Wong BH, Morrice N, MacKintosh C. 14-3-3s regulate fructose-2, 6-bisphosphate levels by binding to PKB-phosphorylated cardiac fructose-2, 6-bisphosphate kinase/phosphatase. EMBO J. 2003;22:3514-3523. doi: 10.1093/emboj/cdg363.
89. Ren J, Samson WK, Sowers JR. Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol. 1999;31:2049-2061.
90. Pentassuglia L, Heim P, Lebboukh S, Morandi C, Xu L, Brink M. Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat car-diomyocytes. Am J Physiol Endocrinol Metab. 2016;310:E782-E794. doi: 10.1152/ajpendo.00259.2015.
91. Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem. 1997;272:17269-17275.
92. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541-6551.
93. Mouton V, Toussaint L, Vertommen D, Gueuning MA, Maisin L, Havaux X, Sanchez-Canedo C, Bertrand L, Dequiedt F, Hemmings BA, Hue L, Rider MH. Heart 6-phosphofructo-2-kinase activation by insulin requires PKB (protein kinase B), but not SGK3 (serum-and glucocorticoid-induced protein kinase 3). Biochem J. 2010;431:267-275. doi: 10.1042/BJ20101089.
94. Donath MY, Jenni R, Brunner HP, Anrig M, Kohli S, Glatz Y, Froesch ER. Cardiovascular and metabolic effects of insulin-like growth factor I at rest and during exercise in humans. J Clin Endocrinol Metab. 1996;81:4089-4094. doi: 10.1210/jcem.81.11.8923865.
95. Russell-Jones DL, Bates AT, Umpleby AM, Hennessy TR, Bowes SB, Hopkins KD, Jackson N, Kelly J, Shojaee-Moradie F, Jones RH. A com-parison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers. Eur J Clin Invest. 1995;25:403-411.
96. Whitham M, Parker BL, Friedrichsen M, et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018;27:237-251.e4. doi: 10.1016/j.cmet.2017.12.001.
97. Garcia NA, Moncayo-Arlandi J, Sepulveda P, Diez-Juan A. Cardiomyocyte exosomes regulate glycolytic fux in endothelium by di-rect transfer of GLUT transporters and glycolytic enzymes. Cardiovasc Res. 2016;109:397-408. doi: 10.1093/cvr/cvv260.
98. Zhao H, Yang L, Baddour J, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;5:e10250. doi: 10.7554/eLife.10250.
99. Salt IP, Hardie DG. AMP-activated protein kinase: an ubiquitous sig-naling pathway with key roles in the cardiovascular system. Circ Res. 2017;120:1825-1841. doi: 10.1161/CIRCRESAHA.117.309633.
100. Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab. 2003;285:E629-E636. doi: 10.1152/ajpendo.00171.2003.
101. Musi N, Hirshman MF, Arad M, Xing Y, Fujii N, Pomerleau J, Ahmad F, Berul CI, Seidman JG, Tian R, Goodyear LJ. Functional role of AMP-activated protein kinase in the heart during exercise. FEBS Lett. 2005;579:2045-2050. doi: 10.1016/j.febslet.2005.02.052.
102. Dolinsky VW, Dyck JR. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol. 2006;291:H2557-H2569. doi: 10.1152/ajpheart.00329.2006.
103. Yavari A, Bellahcene M, Bucchi A, et al. Mammalian γ2 AMPK regulates intrinsic heart rate. Nat Commun. 2017;8:1258. doi: 10.1038/s41467-017-01342-5.
104. Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator-1alpha expression during thyroid hormone-and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol. 2003;284:C1669-C1677. doi: 10.1152/ajpcell.00409.2002.
105. Shimizu Y, Polavarapu R, Eskla KL, Nicholson CK, Koczor CA, Wang R, Lewis W, Shiva S, Lefer DJ, Calvert JW. Hydrogen sulfde regulates cardiac mitochondrial biogenesis via the activation of AMPK. J Mol Cell Cardiol. 2018;116:29-40. doi: 10.1016/j.yjmcc.2018.01.011.
106. Wang B, Nie J, Wu L, Hu Y, Wen Z, Dong L, Zou MH, Chen C, Wang DW. AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. Circ Res. 2018;122:712-729. doi: 10.1161/CIRCRESAHA.117.312317.
107. Horman S, Beauloye C, Vanoverschelde JL, Bertrand L. AMP-activated protein kinase in the control of cardiac metabolism and remodeling. Curr Heart Fail Rep. 2012;9:164-173. doi: 10.1007/s11897-012-0102-z.
108. Nagendran J, Waller TJ, Dyck JR. AMPK signalling and the control of substrate use in the heart. Mol Cell Endocrinol. 2013;366:180-193. doi: 10.1016/j.mce.2012.06.015.
109. Kim M, Hunter RW, Garcia-Menendez L, Gong G, Yang YY, Kolwicz SC Jr, Xu J, Sakamoto K, Wang W, Tian R. Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circ Res. 2014;114:966-975. doi: 10.1161/CIRCRESAHA.114.302364.
110. Sen S, Kundu BK, Wu HC, et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J Am Heart Assoc. 2013;2:e004796. doi: 10.1161/JAHA.113.004796.
111. Kundu BK, Zhong M, Sen S, Davogustto G, Keller SR, Taegtmeyer H. Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Cardiology. 2015;130:211-220. doi: 10.1159/000369782.
112. Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S. Hexokinase-II positively regulates glucose starvation-induced au-tophagy through TORC1 inhibition. Mol Cell. 2014;53:521-533. doi: 10.1016/j.molcel.2013.12.019.
113. Foryst-Ludwig A, Kreissl MC, Benz V, et al. Adipose tissue lipolysis promotes exercise-induced cardiac hypertrophy involving the lipo-kine C16:1n7-palmitoleate. J Biol Chem. 2015;290:23603-23615. doi: 10.1074/jbc.M115.645341.
114. Riquelme CA, Magida JA, Harrison BC, Wall CE, Marr TG, Secor SM, Leinwand LA. Fatty acids identifed in the Burmese python promote benefcial cardiac growth. Science. 2011;334:528-531. doi: 10.1126/science.1210558.
115. Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW. GPCR-Mediated signaling of metabolites. Cell Metab. 2017;25:777-796. doi: 10.1016/j.cmet.2017.03.008.
116. Bezzerides VJ, Platt C, Lerchenmuller C, Paruchuri K, Oh NL, Xiao C, Cao Y, Mann N, Spiegelman BM, Rosenzweig A. CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury. JCI Insight. 2016;1:e85904.
117. Boström P, Mann N, Wu J, Quintero PA, Plovie ER, Panáková D, Gupta RK, Xiao C, MacRae CA, Rosenzweig A, Spiegelman BM. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell. 2010;143:1072-1083. doi: 10.1016/j.cell.2010.11.036.
118. Brookes PS, Taegtmeyer H. Metabolism: a direct link between car-diac structure and function. Circulation. 2017;136:2158-2161. doi: 10.1161/CIRCULATIONAHA.117.031372.
119. Lerchenmüller C, Rosenzweig A. Mechanisms of exercise-induced cardiac growth. Drug Discov Today. 2014;19:1003-1009. doi: 10.1016/j.drudis.2014.03.010.
120. Coronado M, Fajardo G, Nguyen K, Zhao M, Kooiker K, Jung G, Hu DQ, Reddy S, Sandoval E, Stotland A, Gottlieb RA, Bernstein D. Physiological mitochondrial fragmentation is a normal cardiac adaptation to increased energy demand. Circ Res. 2018;122:282-295. doi: 10.1161/CIRCRESAHA.117.310725.
121. Salabei JK, Hill BG. Mitochondrial fssion induced by platelet-derived growth factor regulates vascular smooth muscle cell bio-energetics and cell proliferation. Redox Biol. 2013;1:542-551. doi: 10.1016/j.redox.2013.10.011.
122. Song M, Franco A, Fleischer JA, Zhang L, Dorn GW II. Abrogating mito-chondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab. 2017;26:872-883.e5. doi: 10.1016/j.cmet.2017.09.023.
123. Burman JL, Pickles S, Wang C, Sekine S, Vargas JNS, Zhang Z, Youle AM, Nezich CL, Wu X, Hammer JA, Youle RJ. Mitochondrial fssion facilitates the selective mitophagy of protein aggregates. J Cell Biol. 2017;216:3231-3247. doi: 10.1083/jcb.201612106.
124. Noh J, Wende AR, Olsen CD, Kim B, Bevins J, Zhu Y, Zhang QJ, Riehle C, Abel ED. Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochon-drial adaptations. J Mol Cell Cardiol. 2015;89:297-305.
125. Noor E, Eden E, Milo R, Alon U. Central carbon metabolism as a mini-mal biochemical walk between precursors for biomass and energy. Mol Cell. 2010;39:809-820. doi: 10.1016/j.molcel.2010.08.031.
126. Yamamoto T, Takano N, Ishiwata K, Ohmura M, Nagahata Y, Matsuura T, Kamata A, Sakamoto K, Nakanishi T, Kubo A, Hishiki T, Suematsu M. Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Nat Commun. 2014;5:3480. doi: 10.1038/ncomms4480.
127. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA III, Peters EC, Driggers EM, Hsieh-Wilson LC. Phosphofructokinase 1 glycosyl-ation regulates cell growth and metabolism. Science. 2012;337:975-980. doi: 10.1126/science.1222278.
128. Boada J, Roig T, Perez X, Gamez A, Bartrons R, Cascante M, Bermúdez J. Cells overexpressing fructose-2, 6-bisphosphatase showed enhanced pentose phosphate pathway fux and resistance to oxidative stress. FEBS Lett. 2000;480:261-264.
129. Blackmore PF, Shuman EA. Regulation of hepatic altro heptulose 1, 7-bisphosphate levels and control of fux through the pentose pathway by fructose 2, 6-bisphosphate. FEBS Lett. 1982;142:255-259.
130. Cortassa S, Caceres V, Bell LN, O'Rourke B, Paolocci N, Aon MA. From metabolomics to fuxomics: a computational procedure to translate metabolite profles into metabolic fuxes. Biophys J. 2015;108:163-172. doi: 10.1016/j.bpj.2014.11.1857.
131. Gibb AA, Lorkiewicz PK, Zheng YT, Zhang X, Bhatnagar A, Jones SP, Hill BG. Integration of fux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes. Biochem J. 2017;474:2785-2801. doi: 10.1042/BCJ20170474.
132. Jones SP, Zachara NE, Ngoh GA, Hill BG, Teshima Y, Bhatnagar A, Hart GW, Marbán E. Cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation. 2008;117:1172-1182. doi: 10.1161/CIRCULATIONAHA.107.730515.
133. Watson LJ, Long BW, DeMartino AM, Brittian KR, Readnower RD, Brainard RE, Cummins TD, Annamalai L, Hill BG, Jones SP. Cardiomyocyte Ogt is essential for postnatal viability. Am J Physiol Heart Circ Physiol. 2014;306:H142-H153. doi: 10.1152/ajpheart.00438.2013.
134. Belke DD. Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in heart. J Appl Physiol (1985). 2011;111:157-162. doi: 10.1152/japplphysiol. 00147.2011.
135. Bennett CE, Johnsen VL, Shearer J, Belke DD. Exercise training mitigates aberrant cardiac protein O-GlcNAcylation in streptozotocin-induced diabetic mice. Life Sci. 2013;92:657-663. doi: 10.1016/j.lfs.2012.09.007.
136. Medford HM, Porter K, Marsh SA. Immediate effects of a single exercise bout on protein O-GlcNAcylation and chromatin regulation of cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2013;305:H114-H123. doi: 10.1152/ajpheart.00135.2013.
137. Nelson BA, Robinson KA, Koning JS, Buse MG. Effects of exercise and feeding on the hexosamine biosynthetic pathway in rat skeletal muscle. Am J Physiol. 1997;272:E848-E855. doi: 10.1152/ajpendo.1997.272.5.E848.
138. Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD, Thompson CB. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci USA. 2012;109:6904-6909. doi: 10.1073/pnas.1204176109.
139. Guo D, Gu J, Jiang H, Ahmed A, Zhang Z, Gu Y. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension. J Mol Cell Cardiol. 2016;91:179-187. doi: 10.1016/j.yjmcc.2016.01.009.
140. Chung S, Arrell DK, Faustino RS, Terzic A, Dzeja PP. Glycolytic net-work restructuring integral to the energetics of embryonic stem cell cardiac differentiation. J Mol Cell Cardiol. 2010;48:725-734. doi: 10.1016/j.yjmcc.2009.12.014.
141. Kalhan SC, Hanson RW. Resurgence of serine: an often neglected but indispensable amino Acid. J Biol Chem. 2012;287:19786-19791. doi: 10.1074/jbc.R112.357194.
142. Morland C, Andersson KA, Haugen ØP, et al. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun. 2017;8:15557. doi: 10.1038/ncomms15557.
143. De Bock K, Georgiadou M, Schoors S, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell. 2013;154:651-663. doi: 10.1016/j.cell.2013.06.037.
144. Xu Y, An X, Guo X, et al. Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol. 2014;34:1231-1239. doi: 10.1161/ATVBAHA.113.303041.
145. Vujic A, Lerchenmüller C, Wu TD, Guillermier C, Rabolli CP, Gonzalez E, Senyo SE, Liu X, Guerquin-Kern JL, Steinhauser ML, Lee RT, Rosenzweig A. Exercise induces new cardiomyocyte generation in the adult mammalian heart. Nat Commun. 2018;9:1659. doi: 10.1038/s41467-018-04083-1.
146. Burwell CS. Observations on the output of the heart and the pressure in the veins of pregnant women. Trans Am Clin Climatol Assoc. 1934;50:46-49.
147. Hamilton HF. The cardiac output in normal pregnancy; as determined by the Cournand right catheterization technique. J Obstet Gynaecol Br Emp. 1949;56:548-552.
148. Laird-Meeter K, van de Ley G, Bom TH, Wladimiroff JW, Roelandt J. Cardiocirculatory adjustments during pregnancy-an echocardiographic study. Clin Cardiol. 1979;2:328-332.
149. Schannwell CM, Zimmermann T, Schneppenheim M, Plehn G, Marx R, Strauer BE. Left ventricular hypertrophy and diastolic dysfunction in healthy pregnant women. Cardiology. 2002;97:73-78. doi: 10.1159/000057675.
150. Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J. 1992;68:540-543.
151. Chung E, Yeung F, Leinwand LA. Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation. J Appl Physiol (1985). 2012;112:1564-1575. doi: 10.1152/japplphysiol.00027.2012.
152. Eghbali M, Deva R, Alioua A, Minosyan TY, Ruan H, Wang Y, Toro L, Stefani E. Molecular and functional signature of heart hypertrophy during pregnancy. Circ Res. 2005;96:1208-1216. doi: 10.1161/01.RES.0000170652.71414.16.
153. Zentner D, du Plessis M, Brennecke S, Wong J, Grigg L, Harrap SB. Deterioration in cardiac systolic and diastolic function late in normal human pregnancy. Clin Sci (Lond). 2009;116:599-606. doi: 10.1042/CS20080142.
154. Pandey AK, Banerjee AK, Das A, Bhawani G, Kumar A, Majumadar B, Bhattacharya AK. Evaluation of maternal myocardial performance dur-ing normal pregnancy and post partum. Indian Heart J. 2010;62:64-67.
155. Savu O, Jurcu R, Giu§ca S, van Mieghem T, Gussi I, Popescu BA, Ginghina C, Rademakers F, Deprest J, Voigt JU. Morphological and func-tional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging. 2012;5:289-297. doi: 10.1161/CIRCIMAGING.111.970012.
156. Mone SM, Sanders SP, Colan SD. Control mechanisms for physiological hypertrophy of pregnancy. Circulation. 1996;94:667-672.
157. Bett GC. Hormones and sex differences: changes in cardiac electro-physiology with pregnancy. Clin Sci (Lond). 2016;130:747-759. doi: 10.1042/CS20150710.
158. Gowda RM, Khan IA, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac ar-rhythmias in pregnancy: clinical and therapeutic considerations. Int J Cardiol. 2003;88:129-133.
159. Li J, Umar S, Iorga A, Youn JY, Wang Y, Regitz-Zagrosek V, Cai H, Eghbali M. Cardiac vulnerability to ischemia/reperfusion injury drastically increases in late pregnancy. Basic Res Cardiol. 2012;107:271. doi: 10.1007/s00395-012-0271-7.
160. Li J, Ruffenach G, Kararigas G, Cunningham CM, Motayagheni N, Barakai N, Umar S, Regitz-Zagrosek V, Eghbali M. Intralipid protects the heart in late pregnancy against ischemia/reperfusion injury via Caveolin2/STAT3/GSK-3|3 pathway. J Mol Cell Cardiol. 2017;102:108-116. doi: 10.1016/j.yjmcc.2016.11.006.
161. Chung E, Leinwand LA. Pregnancy as a cardiac stress model. Cardiovasc Res. 2014;101:561-570. doi: 10.1093/cvr/cvu013.
162. Umar S, Nadadur R, Iorga A, Amjedi M, Matori H, Eghbali M. Cardiac structural and hemodynamic changes associated with physiological heart hypertrophy of pregnancy are reversed postpartum. J Appl Physiol (1985). 2012;113:1253-1259. doi: 10.1152/japplphysiol. 00549.2012.
163. Hilfker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell. 2007;128:589-600. doi: 10.1016/j.cell.2006.12.036.
164. Chung E, Heimiller J, Leinwand LA. Distinct cardiac transcriptional profles defning pregnancy and exercise. PLoS One. 2012;7:e42297. doi: 10.1371/journal.pone.0042297.
165. Lemmens K, Doggen K, De Keulenaer GW. Activation of the neuregu-lin/ErbB system during physiological ventricular remodeling in pregnancy. Am J Physiol Heart Circ Physiol. 2011;300:H931-H942. doi: 10.1152/ajpheart 00385.2010.
166. Xu H, van Deel ED, Johnson MR, Opic P, Herbert BR, Moltzer E, Sooranna SR, van Beusekom H, Zang WF, Duncker DJ, Roos-Hesselink JW. Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload. Am J Physiol Heart Circ Physiol. 2016;311:H807-H814.
167. Iorga A, Dewey S, Partow-Navid R, Gomes AV, Eghbali M. Pregnancy is associated with decreased cardiac proteasome activity and oxidative stress in mice. PLoS One. 2012;7:e48601. doi: 10.1371/journal.pone.0048601.
168. Xiao J, Li J, Xu T, Lv D, Shen B, Song Y, Xu J. Pregnancy-induced physiological hypertrophy protects against cardiac ischemia-reperfusion injury. Int J Clin Exp Pathol. 2014;7:229-235.
169. Holness MJ, Changani KK, Sugden MC. Progressive suppression of muscle glucose utilization during pregnancy. Biochem J. 1991;280(pt 2):549-552.
170. Sugden MC, Sugden PH, Holness MJ. Lactate utilization by the heart in vivo. Biochem Soc Trans. 1993;21(pt 3):313S.
171. Sugden MC, Holness MJ. Control of muscle pyruvate oxidation during late pregnancy. FEBS Lett. 1993;321:121-126.
172. Sugden MC, Changani KK, Bentley J, Holness MJ. Cardiac glucose me-tabolism during pregnancy. Biochem Soc Trans. 1992;20:195S.
173. Liu LX, Rowe GC, Yang S, et al. PDK4 inhibits cardiac pyruvate oxidation in late pregnancy. Circ Res. 2017;121:1370-1378. doi: 10.1161/CIRCRESAHA.117.311456.
174. Metzger BE, Hare JW, Freinkel N. Carbohydrate metabolism in pregnan-cy. IX. Plasma levels of gluconeogenic fuels during fasting in the rat. J Clin Endocrinol Metab. 1971;33:869-872. doi: 10.1210/jcem-33-5-869.
175. Pinto J, Barros AS, Domingues MR, Goodfellow BJ, Galhano E, Pita C, Almeida Mdo C, Carreira IM, Gil AM. Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine. J Proteome Res. 2015;14:1263-1274. doi: 10.1021/pr5011982.
176. Redondo-Angulo I, Mas-Stachurska A, Sitges M, Tinahones FJ, Giralt M, Villarroya F, Planavila A. Fgf21 is required for cardiac remodeling in pregnancy. Cardiovasc Res. 2017;113:1574-1584. doi: 10.1093/cvr/cvx088.
177. Laughlin MH, Pollock JS, Amann JF, Hollis ML, Woodman CR, Price EM. Training induces nonuniform increases in eNOS content along the coronary arterial tree. J Appl Physiol (1985). 2001;90:501-510. doi: 10.1152/jappl.2001.90.2.501.
178. Zhang QJ, Li QX, Zhang HF, Zhang KR, Guo WY, Wang HC, Zhou Z, Cheng HP, Ren J, Gao F. Swim training sensitizes myocardial response to insulin: role of Akt-dependent eNOS activation. Cardiovasc Res. 2007;75:369-380. doi: 10.1016/j.cardiores.2007.04.015.
179. Williams JG, Ojaimi C, Qanud K, Zhang S, Xu X, Recchia FA, Hintze TH. Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog. Am J Physiol Heart Circ Physiol. 2008;294:H2516-H2523. doi: 10.1152/ajpheart.01196.2007.
180. Soñanez-Organis JG, Godoy-Lugo JA, Hernández-Palomares ML, Rodríguez-Martínez D, Rosas-Rodríguez JA, González-Ochoa G, Virgen-Ortiz A, Ortiz RM. HIF-1α and PPARγ during physiological cardiac hy-pertrophy induced by pregnancy: transcriptional activities and effects on target genes. Gene. 2016;591:376-381. doi: 10.1016/j.gene.2016.06.025.
181. Cuevas-Ramos D, Almeda-Valdés P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA. Exercise increases serum fbroblast growth factor 21 (FGF21) levels. PLoS One. 2012;7:e38022. doi: 10.1371/journal.pone.0038022.
182. Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One. 2013;8:e63517. doi: 10.1371/journal.pone.0063517.
183. Tanimura Y, Aoi W, Takanami Y, Kawai Y, Mizushima K, Naito Y, Yoshikawa T. Acute exercise increases fbroblast growth factor 21 in metabolic organs and circulation. Physiol Rep. 2016;4:e12828. doi: 10.14814/phy2.12828.
184. Jones CT, Rolph TP. Metabolism during fetal life: a functional assess-ment of metabolic development. Physiol Rev. 1985;65:357-430. doi: 10.1152/physrev.1985.65.2.357.
185. Sissman NJ. Developmental landmarks in cardiac morphogenesis: comparative chronology. Am J Cardiol. 1970;25:141-148.
186. Tyser RC, Miranda AM, Chen CM, Davidson SM, Srinivas S, Riley PR. Calcium handling precedes cardiac differentiation to initiate the frst heartbeat. Elife. 2016;5:e17113. doi: 10.7554/eLife.17113.
187. Battaglia FC, Meschia G. Principal substrates of fetal metabolism. Physiol Rev. 1978;58:499-527. doi: 10.1152/physrev.1978.58.2.499.
188. Makinde AO, Kantor PF, Lopaschuk GD. Maturation of fatty acid and carbohydrate metabolism in the newborn heart. Mol Cell Biochem. 1998;188:49-56.
189. Lopaschuk GD, Jaswal JS. Energy metabolic phenotype of the car-diomyocyte during development, differentiation, and postnatal matu-ration. J Cardiovasc Pharmacol. 2010;56:130-140. doi: 10.1097/FJC.0b013e3181e74a14.
190. Widdas WF. Transport mechanisms in the foetus. Br Med Bull. 1961;17:107-111.
191. Bell AW, Hay WW Jr, Ehrhardt RA. Placental transport of nutrients and its implications for fetal growth. J Reprod Fertil Suppl. 1999;54:401-410.
192. Bartelds B, Gratama JW, Knoester H, Takens J, Smid GB, Aarnoudse JG, Heymans HS, Kuipers JR. Perinatal changes in myocardial supply and fux of fatty acids, carbohydrates, and ketone bodies in lambs. Am J Physiol. 1998;274:H1962-H1969.
193. Bartelds B, Knoester H, Beaufort-Krol GC, Smid GB, Takens J, Zijlstra WG, Heymans HS, Kuipers JR. Myocardial lactate metabolism in fetal and newborn lambs. Circulation. 1999;99:1892-1897.
194. Fisher DJ, Heymann MA, Rudolph AM. Myocardial oxygen and car-bohydrate consumption in fetal lambs in utero and in adult sheep. Am J Physiol. 1980;238:H399-H405. doi: 10.1152/ajpheart.1980.238.3.H399.
195. Père MC. Materno-foetal exchanges and utilisation of nutrients by the foetus: comparison between species. Reprod Nutr Dev. 2003;43:1-15.
196. Char VC, Creasy RK. Lactate and pyruvate as fetal metabolic substrates. Pediatr Res. 1976;10:231-234. doi: 10.1203/00006450-197604000-00006.
197. Clark CM Jr. Characterization of glucose metabolism in the isolated rat heart during fetal and early neonatal development. Diabetes. 1973;22:41-49.
198. Hay WW Jr. Recent observations on the regulation of fetal metabolism by glucose. J Physiol. 2006;572:17-24. doi: 10.1113/jphysiol.2006.105072.
199. Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, Zhang D, Cooksey RC, McClain DA, Litwin SE, Taegtmeyer H, Severson D, Kahn CR, Abel ED. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest. 2002;109:629-639.
200. Jolley RL, Cheldelin VH, Newburgh RW. Glucose catabolism in fetal and adult heart. J Biol Chem. 1958;233:1289-1294.
201. Rolph TP, Jones CT, Parry D. Ultrastructural and enzymatic development of fetal guinea pig heart. Am J Physiol. 1982;243:H87-H93. doi: 10.1152/ajpheart.1982.243.1.H87.
202. Smoak IW. Hypoglycemia and embryonic heart development. Front Biosci. 2002;7:d307-d318.
203. Amatayakul O, Cumming GR, Haworth JC. Association of hypoglycae-mia with cardiac enlargement and heart failure in newborn infants. Arch Dis Child. 1970;45:717-720.
204. Corrigan N, Brazil DP, McAuliffe F. Fetal cardiac effects of maternal hyperglycemia during pregnancy. Birth Defects Res A Clin Mol Teratol. 2009;85:523-530. doi: 10.1002/bdra.20567.
205. Nakano H, Minami I, Braas D et al. Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. Elife. 2017;6:e29330. doi: 10.7554/eLife.29330.
206. Papanicolaou KN, Kikuchi R, Ngoh GA, Coughlan KA, Dominguez I, Stanley WC, Walsh K. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res. 2012;111:1012-1026. doi: 10.1161/CIRCRESAHA.112.274142.
207. Kolwicz SC Jr, Purohit S, Tian R. Cardiac metabolism and its interac-tions with contraction, growth, and survival of cardiomyocytes. Circ Res. 2013;113:603-616. doi: 10.1161/CIRCRESAHA.113.302095.
208. Guimarães-Camboa N, Stowe J, Aneas I, Sakabe N, Cattaneo P, Henderson L, Kilberg MS, Johnson RS, Chen J, McCulloch AD, Nobrega MA, Evans SM, Zambon AC. HIF1α represses cell stress pathways to allow proliferation of hypoxic fetal cardiomyocytes. Dev Cell. 2015;33:507-521. doi: 10.1016/j.devcel.2015.04.021.
209. Menendez-Montes I, Escobar B, Palacios B, Gómez MJ, Izquierdo-Garcia JL, Flores L, Jiménez-Borreguero LJ, Aragones J, Ruiz-Cabello J, Torres M, Martin-Puig S. Myocardial VHL-HIF signaling controls an embryonic metabolic switch essential for cardiac maturation. Dev Cell. 2016;39:724-739. doi: 10.1016/j.devcel.2016.11.012.
210. Paige SL, Plonowska K, Xu A, Wu SM. Molecular regulation of cardiomyocyte differentiation. Circ Res. 2015;116:341-353. doi: 10.1161/CIRCRESAHA.116.302752.
211. Martinez SR, Gay MS, Zhang L. Epigenetic mechanisms in heart de-velopment and disease. Drug Discov Today. 2015;20:799-811. doi: 10.1016/j.drudis.2014.12.018.
212. Chang CP, Bruneau BG. Epigenetics and cardiovascular development. Annu Rev Physiol. 2012;74:41-68. doi: 10.1146/annurev-physiol-020911-153242.
213. Burridge PW, Sharma A, Wu JC. Genetic and epigenetic regulation of human cardiac reprogramming and differentiation in regenerative medicine. Annu Rev Genet. 2015;49:461-484. doi: 10.1146/annurev-genet-112414-054911.
214. Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res. 2015;116:715-736. doi: 10.1161/CIRCRESAHA.116.303936.
215. Laczy B, Hill BG, Wang K, Paterson AJ, White CR, Xing D, Chen YF, Darley-Usmar V, Oparil S, Chatham JC. Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system. Am J Physiol Heart Circ Physiol. 2009;296:H13-H28. doi: 10.1152/ajpheart.01056.2008.
216. Hanover JA, Krause MW, Love DC. Bittersweet memories: linking me-tabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13:312-321. doi: 10.1038/nrm3334.
217. Chen Q, Chen Y, Bian C, Fujiki R, Yu X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature. 2013;493:561-564. doi: 10.1038/nature11742.
218. Jang H, Kim TW, Yoon S, Choi SY, Kang TW, Kim SY, Kwon YW, Cho EJ, Youn HD. O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell. 2012;11:62-74. doi: 10.1016/j.stem.2012.03.001.
219. Huang H, Sabari BR, Garcia BA, Allis CD, Zhao Y. SnapShot: histone mod-ifcations. Cell. 2014;159:458-458.e1. doi: 10.1016/j.cell.2014.09.037.
220. Ritterhoff J, Tian R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc Res. 2017;113:411-421. doi: 10.1093/cvr/cvx017.
221. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093-1129. doi: 10.1152/physrev.00006.2004.
222. Taegtmeyer H, Sen S, Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci. 2010;1188:191-198. doi: 10.1111/j.1749-6632.2009.05100.x.
223. Neubauer S. The failing heart-an engine out of fuel. N Engl J Med. 2007;356:1140-1151. doi: 10.1056/NEJMra063052.
224. Ingwall JS. Energy metabolism in heart failure and remodelling. Cardiovasc Res. 2009;81:412-419. doi: 10.1093/cvr/cvn301.
225. Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G, Opie L. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383:1933-1943. doi: 10.1016/S0140-6736(14)60107-0.
226. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2002;40:271-277.
227. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, Gastaldelli A, Ciociaro D, Pellegrini P, Testa R, Menichetti L, L'Abbate A, Stanley WC, Recchia FA. Impaired myocardial metabolic reserve and substrate selection fexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2007;293:H3270-H3278. doi: 10.1152/ajpheart.00887.2007.
228. de las Fuentes L, Herrero P, Peterson LR, Kelly DP, Gropler RJ, Dávila-Román VG. Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease. Hypertension. 2003;41:83-87.
229. Otsuka Y, Nakatani S, Fukuchi K, Yasumura Y, Komamura K, Yamagishi M, Shimotsu Y, Miyatake K, Ishida Y. Clinical signifcance of iodine-123-15-(p-iodophenyl)-3-R, S-methylpentadecanoic acid myocardial scintigraphy in patients with aortic valve disease. Circ J. 2002;66:41-46.
230. Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fuoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med. 2001;42:55-62.
231. Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Total-body and myo-cardial substrate oxidation in congestive heart failure. Metabolism. 1994;43:174-179.
232. Lommi J, Kupari M, Yki-Järvinen H. Free fatty acid kinetics and oxidation in congestive heart failure. Am J Cardiol. 1998;81:45-50.
233. Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, Karpe F. Substrate utilization by the failing human heart by direct quan-tifcation using arterio-venous blood sampling. PLoS One. 2009;4:e7533. doi: 10.1371/journal.pone.0007533.
234. Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004;287:H1538-H1543. doi: 10.1152/ajpheart.00281.2004.
235. Heather LC, Cole MA, Lygate CA, Evans RD, Stuckey DJ, Murray AJ, Neubauer S, Clarke K. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res. 2006;72:430-437. doi: 10.1016/j.cardiores.2006.08.020.
236. 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;94:2837-2842.
237. Cordero-Reyes AM, Gupte AA, Youker KA, Loebe M, Hsueh WA, Torre-Amione G, Taegtmeyer H, Hamilton DJ. Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function. J Mol Cell Cardiol. 2014;68:98-105. doi: 10.1016/j.yjmcc.2013.12.029.
238. Heather LC, Howell NJ, Emmanuel Y, Cole MA, Frenneaux MP, Pagano D, Clarke K. Changes in cardiac substrate transporters and metabolic proteins mirror the metabolic shift in patients with aortic stenosis. PLoS One. 2011;6:e26326. doi: 10.1371/journal.pone.0026326.
239. Stride N, Larsen S, Hey-Mogensen M, Sander K, Lund JT, Gustafsson F, Køber L, Dela F. Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction. Eur J Heart Fail. 2013;15:150-157. doi: 10.1093/eurjhf/hfs172.
240. Heather LC, Carr CA, Stuckey DJ, Pope S, Morten KJ, Carter EE, Edwards LM, Clarke K. Critical role of complex III in the early metabolic changes following myocardial infarction. Cardiovasc Res. 2010;85:127-136. doi: 10.1093/cvr/cvp276.
241. Akki A, Smith K, Seymour AM. Compensated cardiac hypertrophy is characterised by a decline in palmitate oxidation. Mol Cell Biochem. 2008;311:215-224. doi: 10.1007/s11010-008-9711-y.
242. Zhang L, Jaswal JS, Ussher JR, Sankaralingam S, Wagg C, Zaugg M, Lopaschuk GD. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail. 2013;6:1039-1048. doi: 10.1161/CIRCHEARTFAILURE.112.000228.
243. Paternostro G, Camici PG, Lammerstma AA, Marinho N, Baliga RR, Kooner JS, Radda GK, Ferrannini E. Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography. J Clin Invest. 1996;98:2094-2099. doi: 10.1172/JCI119015.
244. Sansbury BE, DeMartino AM, Xie Z, Brooks AC, Brainard RE, Watson LJ, DeFilippis AP, Cummins TD, Harbeson MA, Brittian KR, Prabhu SD, Bhatnagar A, Jones SP, Hill BG. Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. Circ Heart Fail. 2014;7:634-642. doi: 10.1161/CIRCHEARTFAILURE.114.001151.
245. Chokshi A, Drosatos K, Cheema FH, et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation. 2012;125:2844-2853. doi: 10.1161/CIRCULATIONAHA.111.060889.
246. Mori J, Basu R, McLean BA, Das SK, Zhang L, Patel VB, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY. 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. 2012;5:493-503. doi: 10.1161/CIRCHEARTFAILURE.112.966705.
247. Lommi J, Kupari M, Koskinen P, Näveri H, Leinonen H, Pulkki K, Härkönen M. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol. 1996;28:665-672.
248. Lommi J, Koskinen P, Näveri H, Härkönen M, Kupari M. Heart failure ketosis. J Intern Med. 1997;242:231-238.
249. Bedi KC Jr, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, Wang LL, Javaheri A, Blair IA, Margulies KB, Rame JE. Evidence for intramyocardial disruption of lipid metabolism and increased myocar-dial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-716. doi: 10.1161/CIRCULATIONAHA.115.017545.
250. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Kruger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705.
251. Russell RR III, Cline GW, Guthrie PH, Goodwin GW, Shulman GI, Taegtmeyer H. Regulation of exogenous and endogenous glucose metabolism by insulin and acetoacetate in the isolated working rat heart. A three tracer study of glycolysis, glycogen metabolism, and glucose oxidation. J Clin Invest. 1997;100:2892-2899. doi: 10.1172/JCI119838.
252. Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J. Nutrit. 2006;136:207S-211S.
253. Wang W, Zhang F, Xia Y, Zhao S, Yan W, Wang H, Lee Y, Li C, Zhang L, Lian K, Gao E, Cheng H, Tao L. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol. 2016;311:H1160-H1169. doi: 10.1152/ajpheart.00114.2016.
254. Sun H, Olson KC, Gao C, et al. Catabolic defect of branched-chain ami-no acids promotes heart failure. Circulation. 2016;133:2038-2049. doi: 10.1161/CIRCULATIONAHA.115.020226.
255. Zhang J, Duncker DJ, Ya X, Zhang Y, Pavek T, Wei H, Merkle H, Ugurbil K, From AH, Bache RJ. Effect of left ventricular hypertrophy secondary to chronic pressure overload on transmural myocardial 2-deoxyglucose uptake. A 31P NMR spectroscopic study. Circulation. 1995;92:1274-1283.
256. Tian R, Musi N, D'Agostino J, Hirshman MF, Goodyear LJ. Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation. 2001;104: 1664-1669.
257. Nascimben L, Ingwall JS, Lorell BH, Pinz I, Schultz V, Tornheim K, Tian R. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension. 2004;44:662-667. doi: 10.1161/01.HYP. 0000144292.69599.0c.
258. Kagaya Y, Kanno Y, Takeyama D, Ishide N, Maruyama Y, Takahashi T, Ido T, Takishima T. Effects of long-term pressure overload on regional myocardial glucose and free fatty acid uptake in rats. A quantitative au-toradiographic study. Circulation. 1990;81:1353-1361.
259. Taegtmeyer H, Golfman L, Sharma S, Razeghi P, van Arsdall M. Linking gene expression to function: metabolic fexibility in the normal and diseased heart. Ann N Y Acad Sci. 2004;1015:202-213. doi: 10.1196/annals.1302.017.
260. Kolwicz SC Jr, Tian R. Glucose metabolism and cardiac hypertrophy. Cardiovasc Res. 2011;90:194-201. doi: 10.1093/cvr/cvr071.
261. Liao R, Jain M, Cui L, D'Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R. Cardiac-specifc overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation. 2002;106:2125-2131.
262. Pereira RO, Wende AR, Olsen C, Soto J, Rawlings T, Zhu Y, Anderson SM, Abel ED. Inducible overexpression of GLUT1 prevents mitochon-drial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction. J Am Heart Assoc. 2013;2:e000301. doi: 10.1161/JAHA.113.000301.
263. Pereira RO, Wende AR, Olsen C, Soto J, Rawlings T, Zhu Y, Riehle C, Abel ED. GLUT1 defciency in cardiomyocytes does not accelerate the transition from compensated hypertrophy to heart failure. J Mol Cell Cardiol. 2014;72:95-103.
264. Abel ED, Kaulbach HC, Tian R, Hopkins JC, Duffy J, Doetschman T, Minnemann T, Boers ME, Hadro E, Oberste-Berghaus C, Quist W, Lowell BB, Ingwall JS, Kahn BB. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J Clin Invest. 1999;104:1703-1714.
265. Wende AR, Kim J, Holland WL, Wayment BE, O'Neill BT, Tuinei J, Brahma MK, Pepin ME, McCrory MA, Luptak I, Halade GV, Litwin SE, Abel ED. Glucose transporter 4-defcient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses. Am J Physiol Heart Circ Physiol. 2017;313:H1098-H1108.
266. McCommis KS, Douglas DL, Krenz M, Baines CP. Cardiac-specifc hexokinase 2 overexpression attenuates hypertrophy by increasing pen-tose phosphate pathway fux. J Am Heart Assoc. 2013;2:e000355. doi: 10.1161/JAHA.113.000355.
267. Wang Q, Donthi RV, Wang J, Lange AJ, Watson LJ, Jones SP, Epstein PN. Cardiac phosphatase-defcient 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia. Am J Physiol Heart Circ Physiol. 2008;294:H2889-H2897. doi: 10.1152/ajpheart.91501.2007.
268. Donthi RV, Ye G, Wu C, McClain DA, Lange AJ, Epstein PN. Cardiac expression of kinase-defcient 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity. J Biol Chem. 2004;279:48085-48090. doi: 10.1074/jbc.M405510200.
269. Rees ML, Subramaniam J, Li Y, Hamilton DJ, Frazier OH, Taegtmeyer H. A PKM2 signature in the failing heart. Biochem Biophys Res Commun. 2015;459:430-436. doi: 10.1016/j.bbrc.2015.02.122.
270. Dayton TL, Jacks T, Vander Heiden MG. PKM2, cancer metabolism, and the road ahead. EMBO Rep. 2016;17:1721-1730. doi: 10.15252/embr.201643300.
271. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice iso-form of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230-233. doi: 10.1038/nature06734.
272. Taegtmeyer H, Karlstaedt A, Rees ML, Davogustto G. Oncometabolic tracks in the heart. Circ Res. 2017;120:267-269. doi: 10.1161/CIRCRESAHA. 116.310115.
273. Hecker PA, Leopold JA, Gupte SA, Recchia FA, Stanley WC. Impact of glucose-6-phosphate dehydrogenase defciency on the pathophysi-ology of cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304:H491-H500. doi: 10.1152/ajpheart.00721.2012.
274. Jain M, Brenner DA, Cui L, Lim CC, Wang B, Pimentel DR, Koh S, Sawyer DB, Leopold JA, Handy DE, Loscalzo J, Apstein CS, Liao R. Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes. Circ Res. 2003;93:e9-e16. doi: 10.1161/01.RES.0000083489.83704.76.
275. Jain M, Cui L, Brenner DA, Wang B, Handy DE, Leopold JA, Loscalzo J, Apstein CS, Liao R. Increased myocardial dysfunction after ischemia-reperfusion in mice lacking glucose-6-phosphate de-hydrogenase. Circulation. 2004;109:898-903. doi: 10.1161/01.CIR. 0000112605.43318.CA.
276. Gupte SA, Levine RJ, Gupte RS, Young ME, Lionetti V, Labinskyy V, Floyd BC, Ojaimi C, Bellomo M, Wolin MS, Recchia FA. Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart. J Mol Cell Cardiol. 2006;41:340-349. doi: 10.1016/j.yjmcc.2006.05.003.
277. Vimercati C, Qanud K, Mitacchione G, Sosnowska D, Ungvari Z, Sarnari R, Mania D, Patel N, Hintze TH, Gupte SA, Stanley WC, Recchia FA. Benefcial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart. Am J Physiol Heart Circ Physiol. 2014;306:H709-H717. doi: 10.1152/ajpheart.00783.2013.
278. Dassanayaka S, Jones SP. O-GlcNAc and the cardiovascular system. Pharmacol Ther. 2014;142:62-71. doi: 10.1016/j.pharmthera. 2013.11.005.
279. Mailleux F, Gélinas R, Beauloye C, Horman S, Bertrand L. O-GlcNAcylation, enemy or ally during cardiac hypertrophy development? Biochim Biophys Acta. 2016;1862:2232-2243. doi: 10.1016/j.bbadis. 2016.08.012.
280. Wright JN, Collins HE, Wende AR, Chatham JC. O-GlcNAcylation and cardiovascular disease. Biochem Soc Trans. 2017;45:545-553. doi: 10.1042/BST20160164.
281. Zou L, Zhu-Mauldin X, Marchase RB, Paterson AJ, Liu J, Yang Q, Chatham JC. Glucose deprivation-induced increase in protein O-GlcNAcylation in cardiomyocytes is calcium-dependent. J Biol Chem. 2012;287:34419-34431. doi: 10.1074/jbc.M112.393207.
282. Dennis JW, Lau KS, Demetriou M, Nabi IR. Adaptive regulation at the cell surface by N-glycosylation. Traffc. 2009;10:1569-1578. doi: 10.1111/j.1600-0854.2009.00981.x.
283. Eisenhaber B, Maurer-Stroh S, Novatchkova M, Schneider G, Eisenhaber F. Enzymes and auxiliary factors for GPI lipid anchor biosynthesis and post-translational transfer to proteins. Bioessays. 2003;25:367-385. doi: 10.1002/bies.10254.
284. Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 2009;9:512-524. doi: 10.1016/j.cmet.2009.05.005.
285. Salabei JK, Lorkiewicz PK, Mehra P, Gibb AA, Haberzettl P, Hong KU, Wei X, Zhang X, Li Q, Wysoczynski M, Bolli R, Bhatnagar A, Hill BG. Type 2 diabetes dysregulates glucose metabolism in cardiac progenitor cells. J Biol Chem. 2016;291:13634-13648. doi: 10.1074/jbc.M116.722496.
286. Gao X, Reid MA, Kong M, Locasale JW. Metabolic interactions with cancer epigenetics. Mol Aspects Med. 2017;54:50-57. doi: 10.1016/j.mam.2016.09.001.
287. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51:600-606. doi: 10.1016/j.yjmcc.2010.10.033.
288. Bernard K, Logsdon NJ, Ravi S, Xie N, Persons BP, Rangarajan S, Zmijewski JW, Mitra K, Liu G, Darley-Usmar VM, Thannickal VJ. Metabolic reprogramming is required for myofbroblast contractility and differentiation. J Biol Chem. 2015;290:25427-25438. doi: 10.1074/jbc.M115.646984.
289. Bernard K, Logsdon NJ, Benavides GA, Sanders Y, Zhang J, Darley-Usmar VM, Thannickal VJ. Glutaminolysis is required for transforming growth factor-β1-induced myofbroblast differentiation and activation. J Biol Chem. 2018;293:1218-1228. doi: 10.1074/jbc.RA117.000444.
290. Nigdelioglu R, Hamanaka RB, Meliton AY, O'Leary E, Witt LJ, Cho T, Sun K, Bonham C, Wu D, Woods PS, Husain AN, Wolfgeher D, Dulin NO, Chandel NS, Mutlu GM. Transforming growth factor (TGF)-β promotes de novo serine synthesis for collagen production. J Biol Chem. 2016;291:27239-27251. doi: 10.1074/jbc.M116.756247.
291. Markovitz LJ, Hasin Y, Dann EJ, Gotsman MS, Freund HR. The differ-ent effects of leucine, isoleucine, and valine on systolic properties of the normal and septic isolated rat heart. J Surg Res. 1985;38:231-236.
292. Goldfarb RD, Weber P, Eisenman J. Isolation of a shock-induced circu-lating cardiodepressant substance. Am J Physiol. 1979;237:H168-H177. doi: 10.1152/ajpheart.1979.237.2.H168.
293. Jackson RH, Singer TP. Inactivation of the 2-ketoglutarate and pyruvate dehydrogenase complexes of beef heart by branched chain keto acids. J Biol Chem. 1983;258:1857-1865.
294. Williamson JR, Wałajtys-Rode E, Coll KE. Effects of branched chain alpha-ketoacids on the metabolism of isolated rat liver cells. I. Regulation of branched chain alpha-ketoacid metabolism. J Biol Chem. 1979;254:11511-11520.
295. Li T, Zhang Z, Kolwicz SC Jr, Abell L, Roe ND, Kim M, Zhou B, Cao Y, Ritterhoff J, Gu H, Raftery D, Sun H, Tian R. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 2017;25:374-385. doi: 10.1016/j.cmet.2016.11.005.
296. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009;119:1678-1687. doi: 10.1172/JCI38151.
297. Chua B, Siehl DL, Morgan HE. Effect of leucine and metabolites of branched chain amino acids on protein turnover in heart. J Biol Chem. 1979;254:8358-8362.
298. Chua BH, Siehl DL, Morgan HE. A role for leucine in regulation of pro-tein turnover in working rat hearts. Am J Physiol. 1980;239:E510-E514. doi: 10.1152/ajpendo.1980.239.6.E510.
299. Sciarretta S, Volpe M, Sadoshima J. Mammalian target of rapamycin sig-naling in cardiac physiology and disease. Circ Res. 2014;114:549-564. doi: 10.1161/CIRCRESAHA.114.302022.
300. Kolwicz SC Jr, Olson DP, Marney LC, Garcia-Menendez L, Synovec RE, Tian R. Cardiac-specifc deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res. 2012;111:728-738. doi: 10.1161/CIRCRESAHA.112.268128.
301. Choi YS, de Mattos AB, Shao D, Li T, Nabben M, Kim M, Wang W, Tian R, Kolwicz SC Jr. Preservation of myocardial fatty acid oxidation pre-vents diastolic dysfunction in mice subjected to angiotensin II infusion. J Mol Cell Cardiol. 2016;100:64-71. doi: 10.1016/j.yjmcc.2016.09.001.
302. Bernardo BC, Weeks KL, Pongsukwechkul T, Gao X, Kiriazis H, Cemerlang N, Boey EJ, Tham YK, Johnson CJ, Qian H, Du XJ, Gregorevic P, McMullen JR. Gene delivery of medium chain acyl-coenzyme A dehydrogenase (MCAD) induces physiological cardiac hypertrophy and protects against pathological remodelling. Clin. Sci. 2018;132:381-397.
303. Tolwani RJ, Hamm DA, Tian L, Sharer JD, Vockley J, Rinaldo P, Matern D, Schoeb TR, Wood PA. Medium-chain acyl-CoA dehydro-genase defciency in gene-targeted mice. PLoS Genet. 2005;1:e23. doi: 10.1371/journal.pgen.0010023.
304. Berthiaume JM, Bray MS, McElfresh TA, Chen X, Azam S, Young ME, Hoit BD, Chandler MP. The myocardial contractile response to physiological stress improves with high saturated fat feeding in heart failure. Am J Physiol Heart Circ Physiol. 2010;299:H410-H421. doi: 10.1152/ajpheart.00270.2010.
305. Christopher BA, Huang HM, Berthiaume JM, McElfresh TA, Chen X, Croniger CM, Muzic RF Jr, Chandler MP. Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function. Am J Physiol Heart Circ Physiol. 2010;299:H1917-H1927. doi: 10.1152/ajpheart.00687.2010.
306. Berthiaume JM, Young ME, Chen X, McElfresh TA, Yu X, Chandler MP. Normalizing the metabolic phenotype after myocardial infarction: impact of subchronic high fat feeding. J Mol Cell Cardiol. 2012;53:125-133. doi: 10.1016/j.yjmcc.2012.04.005.
307. Tuunanen H, Engblom E, Naum A, Scheinin M, Någren K, Airaksinen J, Nuutila P, Iozzo P, Ukkonen H, Knuuti J. Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction. J Card Fail. 2006;12:644-652. doi: 10.1016/j.cardfail.2006.06.005.
308. Uchihashi M, Hoshino A, Okawa Y et al. Cardiac-specifc Bdh1 overex-pression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. Circ Heart Fail. 2017;10:e004417. doi: 10.1161/CIRCHEARTFAILURE.117.004417.
309. Schugar RC, Moll AR, André d'Avignon D, Weinheimer CJ, Kovacs A, Crawford PA. Cardiomyocyte-specifc defciency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab. 2014;3:754-769. doi: 10.1016/j.molmet.2014.07.010.
310. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109:121-130. doi: 10.1172/JCI14080.
311. Park SY, Cho YR, Finck BN, et al. Cardiac-specifc overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resis-tance in heart and liver. Diabetes. 2005;54:2514-2524.
312. Aubert G, Vega RB, Kelly DP. Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart. Biochim Biophys Acta. 2013;1833:840-847. doi: 10.1016/j.bbamcr. 2012.08.015.
313. Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276: 37731-37734.
314. Madrazo JA, Kelly DP. The PPAR trio: regulators of myocardial energy metabolism in health and disease. J Mol Cell Cardiol. 2008;44:968-975. doi: 10.1016/j.yjmcc.2008.03.021.
315. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989;38:1124-1144.
316. Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kita T, Kimura T, Shioi T. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail. 2010;3:420-430. doi: 10.1161/CIRCHEARTFAILURE.109.888479.
317. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloro-acetate in coronary artery disease. Am J Cardiol. 1988;61:65-70.
318. Bersin RM, Wolfe C, Kwasman M, Lau D, Klinski C, Tanaka K, Khorrami P, Henderson GN, de Marco T, Chatterjee K. Improved hemo-dynamic function and mechanical effciency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol. 1994;23:1617-1624.
319. Matsuhashi T, Hishiki T, Zhou H, et al. Activation of pyruvate dehy-drogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart. J Mol Cell Cardiol. 2015;82:116-124. doi: 10.1016/j.yjmcc.2015.02.021.
320. Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Trimetazidine, a metabolic modulator, has cardiac and ex-tracardiac benefts in idiopathic dilated cardiomyopathy. Circulation. 2008;118:1250-1258. doi: 10.1161/CIRCULATIONAHA.108.778019.
321. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin. 2012;8:619-631. doi: 10.1016/j.hfc.2012.06.007.
322. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res. 1997;34:25-33.
323. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2006;291:H1489-H1506. doi: 10.1152/ajpheart.00278.2006.
324. Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, Yoshimura M, Yasue H. The diabetic heart utilizes ke-tone bodies as an energy source. Metabolism. 2017;77:65-72. doi: 10.1016/j.metabol.2017.08.005.
325. Chatham JC, Gao ZP, Bonen A, Forder JR. Preferential inhibition of lactate oxidation relative to glucose oxidation in the rat heart following diabetes. Cardiovasc Res. 1999;43:96-106.
326. Bockus LB, Matsuzaki S, Vadvalkar SS, Young ZT, Giorgione JR, Newhardt MF, Kinter M, Humphries KM. Cardiac insulin signaling regulates glycolysis through phosphofructokinase 2 content and activity. J Am Heart Assoc. 2017;6:e007159. doi: 10.1161/JAHA.117.007159.
327. Sakamoto J, Barr RL, Kavanagh KM, Lopaschuk GD. Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart. Am J Physiol Heart Circ Physiol. 2000;278:H1196-H1204. doi: 10.1152/ajpheart.2000.278.4.H1196.
328. Rohm M, Savic D, Ball V, Curtis MK, Bonham S, Fischer R, Legrave N, MacRae JI, Tyler DJ, Ashcroft FM. Cardiac dysfunction and metabolic infexibility in a mouse model of diabetes without dyslipidaemia. Diabetes. 2018;67:1057-1067.
329. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev. 2010;90:367-417. doi: 10.1152/physrev.00003.2009.
330. Taha M, Lopaschuk GD. Alterations in energy metabolism in cardiomyop-athies. Ann Med. 2007;39:594-607. doi: 10.1080/07853890701618305.
331. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol. 2014;171:2080-2090. doi: 10.1111/bph.12475.
332. Luiken JJ, Arumugam Y, Dyck DJ, Bell RC, Pelsers MM, Turcotte LP, Tandon NN, Glatz JF, Bonen A. Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J Biol Chem. 2001;276:40567-40573. doi: 10.1074/jbc.M100052200.
333. Coort SL, Hasselbaink DM, Koonen DP, Willems J, Coumans WA, Chabowski A, van der Vusse GJ, Bonen A, Glatz JF, Luiken JJ. Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes. 2004;53:1655-1663.
334. Coort SL, Luiken JJ, van der Vusse GJ, Bonen A, Glatz JF. Increased FAT (fatty acid translocase)/CD36-mediated long-chain fatty acid uptake in cardiac myocytes from obese Zucker rats. Biochem Soc Trans. 2004;32:83-85. doi: 10.1042/bst0320083.
335. Carley AN, Atkinson LL, Bonen A, Harper ME, Kunnathu S, Lopaschuk GD, Severson DL. Mechanisms responsible for enhanced fatty acid utilization by perfused hearts from type 2 diabetic db/db mice. Arch Physiol Biochem. 2007;113:65-75. doi: 10.1080/13813450701422617.
336. Shearer J, Fueger PT, Wang Z, Bracy DP, Wasserman DH, Rottman JN. Metabolic implications of reduced heart-type fatty acid binding protein in insulin resistant cardiac muscle. Biochim Biophys Acta. 2008;1782:586-592. doi: 10.1016/j.bbadis.2008.07.003.
337. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Safftz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest. 2001;107:813-822. doi: 10.1172/JCI10947.
338. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lip-id uptake and produces a cardiomyopathy. J Clin Invest. 2003;111:419-426. doi: 10.1172/JCI16751.
339. Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest. 2012;122:1109-1118. doi: 10.1172/JCI60329.
340. Tsushima K, Bugger H, Wende AR et al. Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifcations of AKAP121, DRP1, and OPA1 that promote mitochondrial fssion. Circ Res. 2018;122:58-73.
341. Fricovsky ES, Suarez J, Ihm SH, Scott BT, Suarez-Ramirez JA, Banerjee I, Torres-Gonzalez M, Wang H, Ellrott I, Maya-Ramos L, Villarreal F, Dillmann WH. Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol. 2012;303:R689-R699. doi: 10.1152/ajpregu.00548.2011.
342. Sochor M, Gonzalez AM, McLean P. Regulation of alternative pathways of glucose metabolism in rat heart in alloxan diabetes: changes in the pentose phosphate pathway. Biochem Biophys Res Commun. 1984;118:110-116.
343. Cotter MA, Cameron NE, Robertson S. Polyol pathway-mediated changes in cardiac muscle contractile properties: studies in streptozotocin-dia-betic and galactose-fed rats. Exp Physiol. 1992;77:829-838.
344. Katare RG, Caporali A, Oikawa A, Meloni M, Emanueli C, Madeddu P. Vitamin B1 analog benfotiamine prevents diabetes-induced diastolic dysfunction and heart failure through Akt/Pim-1-mediated survival pathway. Circ Heart Fail. 2010;3:294-305. doi: 10.1161/CIRCHEARTFAILURE.109.903450.
345. Trueblood N, Ramasamy R. Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. Am J Physiol. 1998;275:H75-H83.
346. Son NH, Ananthakrishnan R, Yu S, Khan RS, Jiang H, Ji R, Akashi H, Li Q, O'Shea K, Homma S, Goldberg IJ, Ramasamy R. Cardiomyocyte al-dose reductase causes heart failure and impairs recovery from ischemia. PLoS One. 2012;7:e46549. doi: 10.1371/journal.pone.0046549.
347. Molgat AS, Tilokee EL, Rafatian G, Vulesevic B, Ruel M, Milne R, Suuronen EJ, Davis DR. Hyperglycemia inhibits cardiac stem cell-mediated cardiac repair and angiogenic capacity. Circulation. 2014;130:S70-S76. doi: 10.1161/CIRCULATIONAHA.113.007908.
348. Rota M, LeCapitaine N, Hosoda T, et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res. 2006;99:42-52. doi: 10.1161/01.RES. 0000231289.63468.08.
349. Katare R, Oikawa A, Cesselli D, Beltrami AP, Avolio E, Muthukrishnan D, Munasinghe PE, Angelini G, Emanueli C, Madeddu P. Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes. Cardiovasc Res. 2013;97:55-65. doi: 10.1093/cvr/cvs291.
350. Willebrands AF, van der Veen KJ. Infuence of substrate on oxygen con-sumption of isolated perfused rat heart. Am J Physiol. 1967;212:1529-1535. doi: 10.1152/ajplegacy.1967.212.6.1529.
351. Goodwin GW, Cohen DM, Taegtmeyer H. [5-3H]glucose overestimates glycolytic fux in isolated working rat heart: role of the pentose phosphate pathway. Am J Physiol Endocrinol Metab. 2001;280:E502-E508. doi: 10.1152/ajpendo.2001.280.3.E502.
352. Varela FG, Maturana HR, Uribe R. Autopoiesis: the organization of living systems, its characterization and a model. Curr Mod Biol. 1974;5:187-196.
353. Maturana HR, Varela FJ. Autopoiesis and Cognition: The Realization of the Living. Dordrecht, Holland; Boston: D. Reidel Pub. Co.; 1980;1-141.
354. Razeto-Barry P. Autopoiesis 40 years later. A review and a reformulation. Orig Life Evol Biosph. 2012;42:543-567. doi: 10.1007/s11084-012-9297-y.
355. Fleischaker G. Autopoiesis in systems analysis: a debate. Int J Gen Syst. 1992;21:131-271.
356. Capra F, Luisi PL. The Systems View of Life: A Unifying Vision. Cambridge, MA: Cambridge University Press; 2014;1-498.
357. Gatherer D, Galpin V. Rosen's (M, R) system in process algebra. BMC Syst Biol. 2013;7:128. doi: 10.1186/1752-0509-7-128.
358. Rosen R. Life Itself: A Comprehensive Inquiry into the Nature, Origin, and Fabrication of Life. New York, NY: Columbia University Press; 1991;1-285.
359. Riggs DW, Yeager RA, Bhatnagar A. Defning the human envirome: an omics approach for assessing the environmental risk of cardiovascular disease. Circ Res. 2018;122:1259-1275. doi: 10.1161/CIRCRESAHA.117.311230.