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Heart Failure Reviews

, Volume 12, Issue 3–4, pp 331–343 | Cite as

Return to the fetal gene program protects the stressed heart: a strong hypothesis

  • Mitra Rajabi
  • Christos Kassiotis
  • Peter Razeghi
  • Heinrich Taegtmeyer
Article

Abstract

A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. A hallmark of fetal metabolism is the predominance of carbohydrates as substrates for energy provision in a relatively hypoxic environment. When the normal heart is exposed to an oxygen rich environment after birth, energy substrate metabolism is rapidly switched to oxidation of fatty acids. This switch goes along with the expression of “adult” isoforms of metabolic enzymes and other proteins. However, the heart retains the ability to return to the “fetal” gene program. Specifically, the fetal gene program is predominant in a variety of pathophysiologic conditions including hypoxia, ischemia, hypertrophy, and atrophy. A common feature of all of these conditions is extensive remodeling, a decrease in the rate of aerobic metabolism in the cardiomyocyte, and an increase in cardiac efficiency. The adaptation is associated with a whole program of cell survival under stress. The adaptive mechanisms are prominently developed in hibernating myocardium, but they are also a feature of the failing heart muscle. We propose that in failing heart muscle at a certain point the fetal gene program is no longer sufficient to support cardiac structure and function. The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood.

Keywords

Fetal heart Hypertrophy Atrophy Hibernating myocardium Heart failure Metabolism 

Abbreviations

ACC

Acetyl-CoA carboxylase

Akt

Protein kinase B

ANF

Atrial natriuretic factor

CIRKO

Specific insulin receptor knock out

COUP-TF

Chicken ovalbumin upstream promoter transcription factor

mCPT I

Muscle carnitine palmitoyl transferase I

4EBP1

Eukaryotic initiation factor-4E (eIF-4E) binding protein 1

FGF-2

Fibroblast growth factor 2

GIK

Glucose, insulin, potassium

GLUT1

Glucose transporter 1

GLUT4

Glucose transporter 4

GS

Glycogen synthase

mGS

Muscle glycogen synthase

HIF

Hypoxia inducible factor

IGF-1

Insulin-like growth factor 1

JAK

Janus kinases

MAP kinase

Mitogen-activated protein kinase

MCD

Malonyl-CoA decarboxylase

MCAD

Medium chain acyl-CoA dehydrogenase

MEF2

Myocyte enhancer factor 2

MHC

Myosin heavy chain

mTOR

Mammalian target of rapamycin

NFAT

Nuclear factor of activated T cells

PDC

Pyruvate dehydrogenase complex

PDK2

Pyruvate dehydrogenase kinase 2

PGC-1

Peroxisome proliferator activated receptor γ coactivator 1

PI3-kinase

Phosphatidylinositol 3 Kinase

PPAR-α

Peroxisome proliferator activated receptor alpha

p70S6K

P70 ribosomal S6 kinase

SERCA

Sarco (endo) plasmic reticulum Ca2+ATPase

Sp1/3

Specificity protein 1/3

SRF

Serum response factor

STAT

Signal Transducers and Activators of Transcription

TR

Thyroid receptor

TRα1

Thyroid receptorα1

TRβ1

Thyroid receptorβ1

UCP3

Uncoupling protein 3

UPP

Ubiquitin proteosome proteolytic

UPS

Ubiquitin proteasome system

Notes

Acknowledgments

The authors are grateful for the editorial assistance of Rebecca Salazar and Roxy A. Tate. This work was funded by Grant RO1 HL/AG 61483 from the National Institutes of Health, Bethesda, MD, and by the MacDonald General Research Fund, St. Luke’s Episcopal Hospital, Houston, TX.

References

  1. 1.
    Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H (2001) Metabolic gene expression in fetal and failing human heart. Circulation 104:2923–2931PubMedGoogle Scholar
  2. 2.
    Fisher DJ, Heymann MA, Rudolph AM (1980) Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. Am J Physiol 238:H399–H405PubMedGoogle Scholar
  3. 3.
    Fisher D, Heymann M, Rudolph A (1981) Myocardial consumption of oxygen and carbohydrates in newborn sheep. Pediatr Res 15:843–846PubMedCrossRefGoogle Scholar
  4. 4.
    Lopaschuk GD, Collins-Nakai RL, Itoi T (1992) Developmental changes in energy substrate use by the heart. Cardiovasc Res 26:1172-1180PubMedGoogle Scholar
  5. 5.
    Bartelds B, Knoester H, Smid GB, Takens J, Visser GH, Penninga L, van der Leij FR, Beaufort-Krol GC, Zijlstra WG, Heymans HS, Kuipers JR (2000) Perinatal changes in myocardial metabolism in lambs. Circulation 102:926–931PubMedGoogle Scholar
  6. 6.
    Bartelds B, Gratama JW, Knoester H, Takens J, Smid GB, Aarnoudse JG, Heymans HS, Kuipers JR (1998) Perinatal changes in myocardial supply and flux of fatty acids, carbohydrates, and ketone bodies in lambs. Am J Physiol 274:H1962–H1969PubMedGoogle Scholar
  7. 7.
    Korvald C, Elvenes OP, Myrmel T (2000) Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol 278:H1345–H1351PubMedGoogle Scholar
  8. 8.
    Goodwin GW, Taylor CS, Taegtmeyer H (1998) Regulation of energy metabolism of the heart during acute increase in heart work. J Biol Chem 273:29530–29539PubMedGoogle Scholar
  9. 9.
    Schipke JD (1994) Cardiac efficiency. Basic Res Cardiol 89:207–240PubMedGoogle Scholar
  10. 10.
    Bing RJ, Siegel A, Ungar I, Gilbert M (1954) Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism. Am J Med 16:504–515PubMedGoogle Scholar
  11. 11.
    Smith R (2007) Parturition. N Engl J Med 356:271–283PubMedGoogle Scholar
  12. 12.
    Lopaschuk GD, Spafford MA, Marsh DR (1991) Glycolysis is predominant source of ATP production immediately after birth. Am J Physiol 261:H1698–H1705PubMedGoogle Scholar
  13. 13.
    Bartelds B, Knoester H, Beaufort-Krol GC, Smid GB, Takens J, Zijlstra WG, Heymans HS, Kuipers JR (1999) Myocardial lactate metabolism in fetal and newborn lambs. Circulation 99:1892–1897PubMedGoogle Scholar
  14. 14.
    Lehman JJ, Kelly DP (2002) Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev 7:175–185PubMedGoogle Scholar
  15. 15.
    Kantor PF, Robertson MA, Coe JY, Lopaschuk GD (1999) Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J Am Coll Cardiol 33:1724–1734PubMedGoogle Scholar
  16. 16.
    Navaratnam V (1987) Heart muscle: ultrastructural studies. Cambridge University Press, New YorkGoogle Scholar
  17. 17.
    Pederson BA, Chen H, Schroeder JM, Shou W, DePaoli-Roach AA, Roach PJ (2004) Abnormal cardiac development in the absence of heart glycogen. Mol Cell Biol 24:7179–7187PubMedGoogle Scholar
  18. 18.
    Scholz TD, Laughlin MR, Balaban RS, Kupriyanov VV, Heineman FW (1995) Effect of substrate on mitochondrial NADH, cytosolic redox state, and phosphorylated compounds in isolated hearts. Am J Physiol 268:H82–H91PubMedGoogle Scholar
  19. 19.
    Scholz TD, Koppenhafer SL, tenEyck CJ, Schutte BC (1998) Ontogeny of malate-aspartate shuttle capacity and gene expression in cardiac mitochondria. Am J Physiol 274:C780–C788PubMedGoogle Scholar
  20. 20.
    Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856PubMedGoogle Scholar
  21. 21.
    Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368PubMedGoogle Scholar
  22. 22.
    Sano M, Izumi Y, Helenius K, Asakura M, Rossi DJ, Xie M, Taffet G, Hu L, Pautler RG, Wilson CR, Boudina S, Abel ED, Taegtmeyer H, Scaglia F, Graham BH, Kralli A, Shimizu N, Tanaka H, Makela TP, Schneider MD (2007) Menage-a-Trois 1 is critical for the transcriptional function of PPARgamma coactivator 1. Cell Metab 5:129–142PubMedGoogle Scholar
  23. 23.
    Onay-Besikci A, Campbell FM, Hopkins TA, Dyck JR, Lopaschuk GD, Onay Besikci A (2003) Relative importance of malonyl CoA and carnitine in maturation of fatty acid oxidation in newborn rabbit heart. Am J Physiol Heart Circ Physiol. 284:H283–H289PubMedGoogle Scholar
  24. 24.
    Young ME, Laws FA, Goodwin GW, Taegtmeyer H (2001) Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem 276:44390–44395PubMedGoogle Scholar
  25. 25.
    Goodwin CW, Mela L, Deutsch C, Forster RE, Miller LD, Kelivoria-Papadopoulos M (1976) Development and adaptation of heart mitochondrial respiratory chain function in fetus and in newborn. Adv Exp Med Biol 75:13–19Google Scholar
  26. 26.
    Rolph T, Jones C, Parry D (1982) Ultrastructural and enzymatic development of fetal guinea pig heart. Am J Physiol 243:H87–H93PubMedGoogle Scholar
  27. 27.
    Wells RJ, Friedman WF, Sobbel BE (1972) Increase oxidative metabolism in the fetal and newborn lamb heart. Am J Physiol 222:1488–1493PubMedGoogle Scholar
  28. 28.
    Smith HE, Page E (1977) Ultrastructural changes in rabbit heart mitochondria during the perinatal period. Neonatal transition to aerobic metabolism Dev Biol 57:109–117PubMedGoogle Scholar
  29. 29.
    Girard J, Ferre P, Pegorier JP, Duee PH (1992) Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol Rev 72:507–562PubMedGoogle Scholar
  30. 30.
    Gibson DM, Harris RA (2002) Metabolic regulation in mammals, Taylor & Francis, London, p 224Google Scholar
  31. 31.
    Taegtmeyer H, Golfman L, Sharma S, Razeghi P, van Arsdall M (2004) Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann N Y Acad Sci 1015:202–213PubMedGoogle Scholar
  32. 32.
    Swynghedauw B (1986) Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev 66:710–771PubMedGoogle Scholar
  33. 33.
    Morkin E (1993) Regulation of myosin heavy chain genes in the heart. Circulation. 87:1451–1460PubMedGoogle Scholar
  34. 34.
    Sassoon DA, Garner I, Buckingham M (1988) Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo. Development 104:155–164PubMedGoogle Scholar
  35. 35.
    Schwartz K, Carrier L, Chassagne C, Wisnewsky C, Boheler KR (1992) Regulation of myosin heavy chain and actin isogenes during cardiac growth and hypertrophy. Symp Soc Exp Biol 46:265–272PubMedGoogle Scholar
  36. 36.
    Everett AW (1986) Isomyosin expression in human heart in early pre- and post-natal life. J Mol Cell Cardiol 18:607–615PubMedGoogle Scholar
  37. 37.
    Lahmers S, Wu Y, Call DR, Labeit S, Granzier H (2004) Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res 94:505–513PubMedGoogle Scholar
  38. 38.
    Opitz CA, Leake MC, Makarenko I, Benes V, Linke WA (2004) Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ Res 94:967–975PubMedGoogle Scholar
  39. 39.
    Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP, Hajjar RJ, Linke WA (2002) Titin isoform switch in ischemic human heart disease. Circulation 106:1333–1341PubMedGoogle Scholar
  40. 40.
    Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H (2002) Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation 106:1384–1389PubMedGoogle Scholar
  41. 41.
    Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA (2004) Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 95:708–716PubMedGoogle Scholar
  42. 42.
    Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL (2004) Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110:155–162PubMedGoogle Scholar
  43. 43.
    Lim CC, Sawyer DB (2005) Modulation of cardiac function: titin springs into action. J Gen Physiol 125:249–252PubMedGoogle Scholar
  44. 44.
    Akazawa H, Komuro I (2003) Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 92:1079–1088PubMedGoogle Scholar
  45. 45.
    Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600PubMedGoogle Scholar
  46. 46.
    Oka T, Xu J, Molkentin JD (2007) Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 18:117–131PubMedGoogle Scholar
  47. 47.
    Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79PubMedGoogle Scholar
  48. 48.
    Morkin E (2000) Control of cardiac myosin heavy chain gene expression. Microsc Res Tech 50:522–531PubMedGoogle Scholar
  49. 49.
    Sack MN, Disch DL, Rockman HA, Kelly DP (1997) A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Proc Natl Acad Sci U S A 94:6438–6443PubMedGoogle Scholar
  50. 50.
    Depre C, Shipley GL, Chen W, Han Q, Doenst T, Moore ML, Stepkowski S, Davies PJ, Taegtmeyer H (1998) Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med 4:1269–1275PubMedGoogle Scholar
  51. 51.
    Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk GD (1994) Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol 267:H742–H750PubMedGoogle Scholar
  52. 52.
    Doenst T, Goodwin GW, Cedars AM, Wang M, Stepkowski S, Taegtmeyer H (2001) Load-induced changes in vivo alter substrate fluxes and insulin responsiveness of rat heart in vitro. Metabolism 50:1083–1090PubMedGoogle Scholar
  53. 53.
    Barger PM, Kelly DP (2000) PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10:238–245PubMedGoogle Scholar
  54. 54.
    van Bilsen M, Van der Vusse GJ, Reneman RS (1998) Transcriptional regulation of metabolic processes: implications for cardiac metabolism. Pflugers Arch 437:2–14PubMedGoogle Scholar
  55. 55.
    Taegtmeyer H (1994) Energy metabolism of the heart: from basic concepts to clinical applications. Curr Prob Cardiol 19:57–116CrossRefGoogle Scholar
  56. 56.
    Dawes GS, Mott JC, Shelley HJ (1959) The importance of cardiac glycogen for the maintenance of life in foetal lambs and newborn animals during anoxia. J Physiol (Lond) 146:516–538Google Scholar
  57. 57.
    Kim SJ, Peppas A, Hong SK, Yang G, Huang Y, Diaz G, Sadoshima J, Vatner DE, Vatner SF (2003) Persistent stunning induces myocardial hibernation and protection: flow/function and metabolic mechanisms. Circ Res 92:1233–1239PubMedGoogle Scholar
  58. 58.
    Depre C, Vanoverschelde JL, Melin JA, Borgers M, Bol A, Ausma J, Dion R, Wijns W (1995) Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol 268:H1265–H1275PubMedGoogle Scholar
  59. 59.
    Taegtmeyer H (2004) Glycogen in the heart—an expanded view. J Mol Cell Cardiol 37:7–10PubMedGoogle Scholar
  60. 60.
    Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr (2003), Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100:3077–3082PubMedGoogle Scholar
  61. 61.
    Chin E, Allen D (1997) Effects of reduced muscle glycogen concentration on force, Ca2+ release and contractile protein function in intact mouse skeletal muscle. J Physiol (Lond) 498:17–29Google Scholar
  62. 62.
    Entman ML, Kanike K, Goldstein MA, Nelson TE, Bornet EP, Futch TW, Schwartz A (1976) Association of glycogenolysis with cardiac sarcoplasmic reticulum. J Biol Chem 251:3140–3146Google Scholar
  63. 63.
    Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145PubMedGoogle Scholar
  64. 64.
    Taegtmeyer H (2004) Cardiac metabolism as a target for the treatment of heart failure. Circulation 110:894–896PubMedGoogle Scholar
  65. 65.
    Semenza GL (2004) O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J Appl Physiol 96:1173–1177; discussion 1170–1172Google Scholar
  66. 66.
    Depre C, Taegtmeyer H (2000) Metabolic aspects of programmed cell survival and cell death in the heart. Cardiovasc Res 45:538–548PubMedGoogle Scholar
  67. 67.
    Schoene RB, Hackett PH, Hornbern TF (2000) High altitude. Murray & Nadel textbook of respiratory medicine, 3rd edn. W. B. Saunders Company, Philadelphia, 1915–1950Google Scholar
  68. 68.
    Razeghi P, Young ME, Abbasi S, Taegtmeyer H (2001) Hypoxia in vivo decreases peroxisome proliferator-activated receptor alpha-regulated gene expression in rat heart. Biochem Biophys Res Commun 287:5–10PubMedGoogle Scholar
  69. 69.
    Sharma S, Taegtmeyer H, Adrogue J, Razeghi P, Sen S, Ngumbela K, Essop MF (2004) Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy. Am J Cardiol Heart Circ Physiol 286:H1185–H192Google Scholar
  70. 70.
    Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, Davies PJ, Taegtmeyer H (2000) Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J Mol Cell Cardiol 32:985–996PubMedGoogle Scholar
  71. 71.
    Young ME, Wilson CR, Razeghi P, Guthrie PH, Taegtmeyer H (2002) Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. J Mol Cell Cardiol 34:223–231PubMedGoogle Scholar
  72. 72.
    Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H (2002) Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106:407–411PubMedGoogle Scholar
  73. 73.
    Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H (2004) Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. Faseb J 18:1692–1700PubMedGoogle Scholar
  74. 74.
    Kurabayashi M, Tsuchimochi H, Komuro I, Takaku F, Yazaki Y (1988) Molecular cloning and characterization of human cardiac alpha- and beta-form myosin heavy chain complementary DNA clones. Regulation of expression during development and pressure overload in human atrium. J Clin Invest 82:524–531PubMedGoogle Scholar
  75. 75.
    Reiser PJ, Portman MA, Ning XH, Schomisch Moravec C (2001) Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol 280:H1814–H1820PubMedGoogle Scholar
  76. 76.
    Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA (1997) Myosin heavy chain gene expression in human heart failure. J Clin Invest 100:2362–2370PubMedCrossRefGoogle Scholar
  77. 77.
    Kinugawa K, Minobe W, Wood W, Ridgway E, Baxter J, Ribeiro R, Tawadrous M, Lowes B, Long C, Bristow M (2001) Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression. Circulation 103:1089–1094PubMedGoogle Scholar
  78. 78.
    Pantos C, Malliopoulou V, Varonos DD, Cokkinos DV (2004) Thyroid hormone and phenotypes of cardioprotection. Basic Res Cardiol 99:101–120PubMedGoogle Scholar
  79. 79.
    Pantos C, Mourouzis I, Saranteas T, Paizis I, Xinaris C, Malliopoulou V, Cokkinos DV (2005) Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion. Basic Res Cardiol 100:422–432PubMedGoogle Scholar
  80. 80.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189PubMedGoogle Scholar
  81. 81.
    Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J (2003) Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92:715–724PubMedGoogle Scholar
  82. 82.
    Heusch G, Schulz R, Rahimtoola SH (2005) Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 288:H984–H999PubMedGoogle Scholar
  83. 83.
    Gottlieb RA (1999) Mitochondria: ignition chamber for apoptosis. Mol Genet Metab 68:227–231PubMedGoogle Scholar
  84. 84.
    Downward J (2003) Metabolism meets death. Nature 424:896–897PubMedGoogle Scholar
  85. 85.
    Depre C, Vatner SF (2005) Mechanisms of cell survival in myocardial hibernation. Trends Cardiovasc Med 15:101–110PubMedGoogle Scholar
  86. 86.
    Gradinac S, Coleman GM, Taegtmeyer H, Sweeney MS, Frazier OH (1989) Improved cardiac function with glucose-insulin-potassium after aortocoronary bypass grafting. Ann Thorac Surg 48:484–489PubMedGoogle Scholar
  87. 87.
    Lazar HL (1997) Enhanced preservation of acutely ischemic myocardium and improved clinical outcomes using glucose-insulin-potassium (GIK) solutions. Am J Cardiol 80:90A–93APubMedGoogle Scholar
  88. 88.
    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367PubMedGoogle Scholar
  89. 89.
    Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354:449–461PubMedGoogle Scholar
  90. 90.
    Ranasinghe AM, Quinn DW, Pagano D, Edwards N, Faroqui M, Graham TR, Keogh BE, Mascaro J, Riddington DW, Rooney SJ, Townend JN, Wilson IC, Bonser RS (2006) Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting. Circulation 114:I245–I250PubMedGoogle Scholar
  91. 91.
    Sack MN, Yellon DM (2003) Insulin therapy as an adjunct to reperfusion after acute coronary ischemia. A proposed direct myocardial cell survival effect independent of metabolic modulation. J Am Coll Cardiol 41:1404–1407PubMedGoogle Scholar
  92. 92.
    Jonassen AK, Mjos OD, Sack MN (2004) p70s6 kinase is a functional target of insulin activated Akt cell-survival signaling. Biochem Biophys Res Commun 315:160–165PubMedGoogle Scholar
  93. 93.
    Matsui T, Nagoshi T, Rosenzweig A (2003) Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2:220–223PubMedGoogle Scholar
  94. 94.
    Matsui T, Li L, Wu J, Cook S, Nagoshi T, Picard M, Liao R, Rosenzweig A (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277:22896–22901PubMedGoogle Scholar
  95. 95.
    Whiteman E, Cho H, Birnbaum M (2002) Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab 13:444–451PubMedGoogle Scholar
  96. 96.
    Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418PubMedGoogle Scholar
  97. 97.
    Majewski N, Nogueira V, Robey RB, Hay N (2004) Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol 24:730–740PubMedGoogle Scholar
  98. 98.
    Cook SA, Matsui T, Li L, Rosenzweig A (2002) Transcriptional effects of chronic Akt activation in the heart. J Biol Chem epub ahead of printGoogle Scholar
  99. 99.
    Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547–555PubMedGoogle Scholar
  100. 100.
    Lewandowski ED, Kudej RK, White LT, O’Donnell JM, Vatner SF (2002) Mitochondrial preference for short chain fatty acid oxidation during coronary artery constriction. Circulation 105:367–372PubMedGoogle Scholar
  101. 101.
    Dewald O, Sharma S, Adrogue J, Salazar R, Duerr GD, Crapo JD, Entman ML, Taegtmeyer H (2005) Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation 112:407–415PubMedGoogle Scholar
  102. 102.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721PubMedGoogle Scholar
  103. 103.
    Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281:29776–29787PubMedGoogle Scholar
  104. 104.
    Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036PubMedGoogle Scholar
  105. 105.
    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111PubMedGoogle Scholar
  106. 106.
    Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 102:13807–13812PubMedGoogle Scholar
  107. 107.
    Lockshin RA, Zakeri Z (2004) Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36:2405–2419PubMedGoogle Scholar
  108. 108.
    Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM (2001) Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51:304–312PubMedGoogle Scholar
  109. 109.
    Mistiaen WP, Somers P, Knaapen MW, Kockx MM (2006) Autophagy as mechanism for cell death in degenerative aortic valve disease. Autophagy 2:221–223PubMedGoogle Scholar
  110. 110.
    Saijo M, Takemura G, Koda M, Okada H, Miyata S, Ohno Y, Kawasaki M, Tsuchiya K, Nishigaki K, Minatoguchi S, Goto K, Fujiwara H (2004) Cardiomyopathy with prominent autophagic degeneration, accompanied by an elevated plasma brain natriuretic peptide level despite the lack of overt heart failure. Intern Med 43:700–703PubMedGoogle Scholar
  111. 111.
    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 (2002) Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 109:629–639PubMedGoogle Scholar
  112. 112.
    Frazier OH, Benedict CR, Radovancevic B, Bick RJ, Capek P, Springer WE, Macris MP, Delgado R, Buja LM (1996) Improved left ventricular function after chronic left ventricular unloading. Ann Thorac Surg 62:1–8Google Scholar
  113. 113.
    Muller J, Wallukat G, Weng YG, Dandel M, Spiegelsberger S, Semrau S, Brandes K, Theodoridis V, Loebe M, Meyer R, Hetzer R (1997) Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation 96:542–549PubMedGoogle Scholar
  114. 114.
    Barton PJ, Felkin LE, Birks EJ, Cullen ME, Banner NR, Grindle S, Hall JL, Miller LW, Yacoub MH (2005) Myocardial insulin-like growth factor-I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy. Circulation 112:I46–I50PubMedGoogle Scholar
  115. 115.
    Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, Banner NR, Khaghani A, Yacoub MH (2006) Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 355:1873–1884PubMedGoogle Scholar
  116. 116.
    Razeghi P, Myers TJ, Frazier OH, Taegtmeyer H (2002) Reverse remodeling of the failing human heart with mechanical unloading. Emerging concepts and unanswered questions. Cardiology 98:167–174PubMedGoogle Scholar
  117. 117.
    Razeghi P, Taegtmeyer H (2006) Hypertrophy and atrophy of the heart: the other side of remodeling. Ann N Y Acad Sci 1080:110–119PubMedGoogle Scholar
  118. 118.
    Sharma S, Ying J, Razeghi P, Stepkowski S, Taegtmeyer H (2006) Atrophic remodeling of the transplanted rat heart. Cardiology 105:128–136PubMedGoogle Scholar
  119. 119.
    Razeghi P, Young ME, Ying J, Depre C, Uray IP, Kolesar J, Shipley GL, Moravec CS, Davies PJ, Frazier OH, Taegtmeyer H (2002) Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading. Cardiology 97:203–209PubMedGoogle Scholar
  120. 120.
    Razeghi P, Sharma S, Ying J, Li YP, Stepkowski S, Reid MB, Taegtmeyer H (2003) Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Circulation 108:2536–2541PubMedGoogle Scholar
  121. 121.
    Schaffer JE (2003) Lipotoxicity: when tissues overeat. Curr Opin Lipidol 14:281–287PubMedGoogle Scholar
  122. 122.
    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 94:2837–2842PubMedGoogle Scholar
  123. 123.
    Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA (2002) Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 106:606–612PubMedGoogle Scholar
  124. 124.
    Davila-Roman VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ (2002) Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 40:271–277PubMedGoogle Scholar
  125. 125.
    Taylor M, Wallhaus T, DeGrado T, Russell D, Stanko P, Nickles R, Stone C (2001) An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro–6-thia-heptadecanoic acid. J Nucl Med 42:55–62PubMedGoogle Scholar
  126. 126.
    Wallhaus TR, Taylor M, DeGrado TR, Russel TC, Stanko P, Nickles RJ, Stone CK (2001) Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 103:2441–2446PubMedGoogle Scholar
  127. 127.
    Taegtmeyer H (2002) Switching metabolic genes to build a better heart. Circulation 106:2043–2045PubMedGoogle Scholar
  128. 128.
    Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD (2006) Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia. Am J Physiol Heart Circ Physiol 290:H87–H95PubMedGoogle Scholar
  129. 129.
    Eichhorn EJ, Bristow MR (1996) Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation 94:2285–2296PubMedGoogle Scholar
  130. 130.
    Katz AM (2001) Heart failure in 2001: a prophecy revisited. Am J Cardiol 87:1383–1386PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Mitra Rajabi
    • 1
  • Christos Kassiotis
    • 1
  • Peter Razeghi
    • 1
  • Heinrich Taegtmeyer
    • 1
  1. 1.Department of Internal Medicine, Division of CardiologyUniversity of Texas-Houston Medical SchoolHoustonUSA

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