The Fetal Phenotype

  • Dennis V. CokkinosEmail author


The fetal phenotype is an adaptation of the heart to stress (heart failure, hypertrophy, remodelling, hibernation diabetes mellitus). The fetal heart represents a “protected” state; thus cell death can be avoided when adverse condition for cardiac intergity occur.

It is characterized by an increase in glycogen and βΜHC, together with ANP expression, and decrease of αMHC. A tissue hypothyroid state is said to occur. 

However, is less efficient in contractility. It may represent a dedifferentiated state which may predispose to cardiomyocyte regeneration. Interestingly, atrophy is also associated with fetal phenotype.


Heart failure Remodeling Diabetes mellitus Glycogen Myosin heavy chain Fibrosis 


  1. 1.
    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;1188:191–8.CrossRefGoogle Scholar
  2. 2.
    Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79:215–62.CrossRefGoogle Scholar
  3. 3.
    Bartelds B, Knoester H, Smid GB, Takens J, Visser GH, Penninga L, et al. Perinatal changes in myocardial metabolism in lambs. Circulation. 2000;102:926–31.CrossRefGoogle Scholar
  4. 4.
    Navaratnam V. Heart muscle: Vetrastructural studies Cambridge. New York: University Press; 1987. referred in 1.Google Scholar
  5. 5.
    Pederson BA, Chen H, Schroeder JM, Shou W, DePaoli-Roach AA, Roach PJ. Abnormal cardiac development in the absence of heart glycogen. Mol Cell Biol. 2004;24:7179–87.CrossRefGoogle Scholar
  6. 6.
    Van der Vusse GJ, Reneman RS. Glycogen and lipids endogeneous substances. In: Drake-Holland A-J, MIM N, editors. Cardiac metabolism. New York: Willey; 1983. p. 215–37.Google Scholar
  7. 7.
    Barbosa V, Sievers RE, Zaugg CE, Wolfe CL. Preconditioning ischemia time determines the degree of glycogen depletion and infarct size reduction in rat hearts. Am Heart J. 1996;131:224–30.CrossRefGoogle Scholar
  8. 8.
    Girard J, Ferré P, Pégorier JP, Duée PH. Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol Rev. 1992;72:507–62.CrossRefGoogle Scholar
  9. 9.
    Goodwin CW, Mela L, Deutsch C, Forster RE, Miller LD, Kelivoria-Papadopoulos M. Development and adaptation of heart mitochondrial respiratory chain function in fetus and in newborn. Adv Exp Med Biol. 1976;75:713–9.CrossRefGoogle Scholar
  10. 10.
    Weitzel JM, Iwen KA, Seitz HJ. Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol. 2003;88:121–8.CrossRefGoogle Scholar
  11. 11.
    Scholz TD, Koppenhafer SL. tenEyck CJ, Schutte BC. Ontogeny of malate-aspartate shuttle capacity and gene expression in cardiac mitochondria. Am J Phys. 1998;274:C780–8.CrossRefGoogle Scholar
  12. 12.
    Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev. 2007;12:331–43.CrossRefGoogle Scholar
  13. 13.
    Taegtmeyer H, Golfman L, Sharma S, Razeghi P, van Arsdall M. Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann N Y Acad Sci. 2004;1015:202–13.CrossRefGoogle Scholar
  14. 14.
    Morkin E. Regulation of myosin heavy chain genes in the heart. Circulation. 1993;87:1451–60.CrossRefGoogle Scholar
  15. 15.
    Krenz M, Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol. 2004;44:2390–7.CrossRefGoogle Scholar
  16. 16.
    Danzi S, Klein S, Klein I. Differential regulation of the myosin heavy chain genes alpha and beta in rat atria and ventricles: role of antisense RNA. Thyroid. 2008;18:761–8.CrossRefGoogle Scholar
  17. 17.
    Fuller GA, Bicer S, Hamlin RL, Yamaguchi M, Reiser PJ. Increased myosin heavy chain-beta with atrial expression of ventricular light chain-2 in canine cardiomyopathy. J Card Fail. 2007;13:680–6.CrossRefGoogle Scholar
  18. 18.
    Narolska NA, van Loon RB, Boontje NM, Zaremba R, Penas SE, Russell J, et al. Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue. Cardiovasc Res. 2005;65:221–9.CrossRefGoogle Scholar
  19. 19.
    Gustafson TA, Bahl JJ, Markham BE, Roeske WR, Morkin E. Hormonal regulation of myosin heavy chain and alpha-actin gene expression in cultured fetal rat heart myocytes. J Biol Chem. 1987;262:13316–22.PubMedGoogle Scholar
  20. 20.
    Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation. 2001;104:2923–31.CrossRefGoogle Scholar
  21. 21.
    Reiser PJ, Portman MA, Ning XH, Schomisch MC. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol. 2001;280:H1814–20.CrossRefGoogle Scholar
  22. 22.
    Morkin E. Control of cardiac myosin heavy chain gene expression. Microsc Res Tech. 2000;50:522–31.CrossRefGoogle Scholar
  23. 23.
    Schwartz K, Boheler KR, de la Bastie D, Lompre AM, Mercadier JJ. Switches in cardiac muscle gene expression as a result of pressure and volume overload. Am J Phys. 1992;262:R364–9.CrossRefGoogle Scholar
  24. 24.
    Lahmers S, Wu Y, Call DR, Labeit S, Granzier H. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res. 2004;94:505–13.CrossRefGoogle Scholar
  25. 25.
    Cameron VA, Ellmers LJ. Natriuretic peptides during development of the fetal heart and circulation. Endocrinology. 2003;144:2191–4.CrossRefGoogle Scholar
  26. 26.
    Kangawa K, Matsuo H. Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha-hANP). Biochem Biophys Res Commun. 1984;118:131–9.CrossRefGoogle Scholar
  27. 27.
    Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev. 1992;44:479–602.PubMedGoogle Scholar
  28. 28.
    Takahashi T, Allen PD, Izumo S. Expression of A-, B-, and C-type natriuretic peptide genes in failing and developing human ventricles. Correlation with expression of the ca(2+)-ATPase gene. Circ Res. 1992;71:9–17.CrossRefGoogle Scholar
  29. 29.
    Gardner DG, Hedges BK, Wu J, LaPointe MC, Deschepper CF. Expression of the atrial natriuretic peptide gene in human fetal heart. J Clin Endocrinol Metab. 1989;69:729–37.CrossRefGoogle Scholar
  30. 30.
    Hersey RM, Nazir MA, Whitney KD, Klein RM, Sale RD, Hinton DA, et al. Atrial natriuretic peptide in heart and specific binding in organs from fetal and newborn rats. Cell Biochem Funct. 1989;7:35–41.CrossRefGoogle Scholar
  31. 31.
    Cameron VA, Aitken GD, Ellmers LJ, Kennedy MA, Espiner EA. The sites of gene expression of atrial, brain, and C-type natriuretic peptides in mouse fetal development: temporal changes in embryos and placenta. Endocrinology. 1996;137:817–24.CrossRefGoogle Scholar
  32. 32.
    Scott JN, Jennes L. Distribution of atrial natriuretic factor in fetal rat atria and ventricles. Cell Tissue Res. 1987;248:479–81.CrossRefGoogle Scholar
  33. 33.
    Day ML, Schwartz D, Wiegand RC, Stockman PT, Brunnert SR, Tolunay HE, et al. Ventricular atriopeptin. Unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone. Hypertension. 1987;9:485–91.CrossRefGoogle Scholar
  34. 34.
    Cameron VA, Rademaker MT, Ellmers LJ, Espiner EA, Nicholls MG, Richards AM. Atrial (ANP) and brain natriuretic peptide (BNP) expression after myocardial infarction in sheep: ANP is synthesized by fibroblasts infiltrating the infarct. Endocrinology. 2000;141:4690–7.CrossRefGoogle Scholar
  35. 35.
    Luchner A, Stevens TL, Borgeson DD, Redfield M, Wei CM, Porter JG, et al. Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure. Am J Phys. 1998;274:H1684–9.Google Scholar
  36. 36.
    Abell TJ, Richards AM, Ikram H, Espiner EA, Yandle T. Atrial natriuretic factor inhibits proliferation of vascular smooth muscle cells stimulated by platelet-derived growth factor. Biochem Biophys Res Commun. 1989;160:1392–6.CrossRefGoogle Scholar
  37. 37.
    Horio T, Nishikimi T, Yoshihara F, Matsuo H, Takishita S, Kangawa K. Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac myocytes. Hypertension. 2000;35:19–24.CrossRefGoogle Scholar
  38. 38.
    Wu CF, Bishopric NH, Pratt RE. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem. 1997;272:14860–6.CrossRefGoogle Scholar
  39. 39.
    Kuhn M, Holtwick R, Baba HA, Perriard JC, Schmitz W, Ehler E. Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart. 2002;87:368–74.CrossRefGoogle Scholar
  40. 40.
    Cox EJ, Marsh SA. A systematic review of fetal genes as biomarkers of cardiac hypertrophy in rodent models of diabetes. PLoS One. 2014;9:e92903.CrossRefGoogle Scholar
  41. 41.
    Periasamy M, Bhupathy P, Babu GJ. Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc Res. 2008;77:265–73.CrossRefGoogle Scholar
  42. 42.
    Rivera-Feliciano J, Lee KH, Kong SW, Rajagopal S, Ma Q, Springer Z, et al. Development of heart valves requires Gata4 expression in endothelial-derived cells. Development. 2006;133:3607–18.CrossRefGoogle Scholar
  43. 43.
    Molkentin JD, Kalvakolanu DV, Markham BE. Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene. Mol Cell Biol. 1994;14:4947–57.CrossRefGoogle Scholar
  44. 44.
    Maitra M, Schluterman MK, Nichols HA, Richardson JA, Lo CW, Srivastava D, et al. Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol. 2009;326:368–77.CrossRefGoogle Scholar
  45. 45.
    Hasegawa K, Lee SJ, Jobe SM, Markham BE, Kitsis RN. Cis-acting sequences that mediate induction of beta-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation. 1997;96:3943–53.CrossRefGoogle Scholar
  46. 46.
    Lien CL, Wu C, Mercer B, Webb R, Richardson JA, Olson EN. Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Development. 1999;126:75–84.PubMedGoogle Scholar
  47. 47.
    Azakie A, Fineman JR, He Y. Myocardial transcription factors are modulated during pathologic cardiac hypertrophy in vivo. J Thorac Cardiovasc Surg. 2006;132:1262–71.CrossRefGoogle Scholar
  48. 48.
    Thattaliyath BD, Firulli BA, Firulli AB. The basic-helix-loop-helix transcription factor HAND2 directly regulates transcription of the atrial naturetic peptide gene. J Mol Cell Cardiol. 2002;34:1335–44.CrossRefGoogle Scholar
  49. 49.
    Kolwicz SC Jr, Tian R. Glucose metabolism and cardiac hypertrophy. Cardiovasc Res. 2011;90:194–201.CrossRefGoogle Scholar
  50. 50.
    Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res. 2008;79:269–78.CrossRefGoogle Scholar
  51. 51.
    Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, et al. Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J Mol Cell Cardiol. 2000;32:985–96.CrossRefGoogle Scholar
  52. 52.
    Dawes GS, Mott JC, Shelley HJ. The importance of cardiac glycogen for the maintenance of life in foetal lambs and newborn animals during anoxia. J Physiol. 1959;146:516–38.CrossRefGoogle Scholar
  53. 53.
    Depré C, Vanoverschelde JL, Melin JA, Borgers M, Bol A, Ausma J, et al. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Phys. 1995;268:H1265–75.Google Scholar
  54. 54.
    Taegtmeyer H. Glycogen in the heart--an expanded view. J Mol Cell Cardiol. 2004;37:7–10.CrossRefGoogle Scholar
  55. 55.
    Kim SJ, Peppas A, Hong SK, Yang G, Huang Y, Diaz G, et al. Persistent stunning induces myocardial hibernation and protection: flow/function and metabolic mechanisms. Circ Res. 2003;92:1233–9.CrossRefGoogle Scholar
  56. 56.
    Kinugawa K, Minobe WA, Wood WM, Ridgway EC, Baxter JD, Ribeiro RC, et al. Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression. Circulation. 2001;103:1089–94.CrossRefGoogle Scholar
  57. 57.
    Pantos C, Mourouzis I, Saranteas T, Paizis I, Xinaris C, Malliopoulou V, et al. Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion. Basic Res Cardiol. 2005;100:422–32.CrossRefGoogle Scholar
  58. 58.
    Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem. 2002;277:22896–901.CrossRefGoogle Scholar
  59. 59.
    Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N, et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001;15:1406–18.CrossRefGoogle Scholar
  60. 60.
    Majewski N, Nogueira V, Robey RB, Hay N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol. 2004;24:730–40.CrossRefGoogle Scholar
  61. 61.
    Baker JE, Holman P, Gross GJ. Preconditioning in immature rabbit hearts: role of KATP channels. Circulation. 1999;99:1249–54.CrossRefGoogle Scholar
  62. 62.
    Baker EJ, Boerboom LE, Olinger GN, Baker JE. Tolerance of the developing heart to ischemia: impact of hypoxemia from birth. Am J Phys. 1995;268:H1165–73.Google Scholar
  63. 63.
    Awad WI, Shattock MJ, Chambers DJ. Ischemic preconditioning in immature myocardium. Circulation. 1998;98:II206–13.PubMedGoogle Scholar
  64. 64.
    Mourouzis I, Dimopoulos A, Saranteas T, Tsinarakis N, Livadarou E, Spanou D, et al. Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart. Physiol Res. 2009;58:29–38.PubMedGoogle Scholar
  65. 65.
    Dirkx E, da Costa Martins PA, De Windt LJ. Regulation of fetal gene expression in heart failure. Biochim Biophys Acta. 1832;2013:2414–24.Google Scholar
  66. 66.
    Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE, Molkentin JD. The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem. 2001;276:30245–302453.CrossRefGoogle Scholar
  67. 67.
    Sepulveda JL, Vlahopoulos S, Iyer D, Belaguli N, Schwartz RJ. Combinatorial expression of GATA4, Nkx2-5, and serum response factor directs early cardiac gene activity. J Biol Chem. 2002;277:25775–257782.CrossRefGoogle Scholar
  68. 68.
    Gusterson RJ, Jazrawi E, Adcock IM, Latchman DS. The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity. J Biol Chem. 2003;278:6838–47.CrossRefGoogle Scholar
  69. 69.
    Kee HJ, Bae EH, Park S, Lee KE, Suh SH, Kim SW, et al. HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity. Kidney Blood Press Res. 2013;37:229–39.CrossRefGoogle Scholar
  70. 70.
    Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 2004;338:17–31.CrossRefGoogle Scholar
  71. 71.
    Eom GH, Cho YK, Ko JH, Shin S, Choe N, Kim Y, et al. Casein kinase-2α1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart. Circulation. 2011;123:2392–403.CrossRefGoogle Scholar
  72. 72.
    Lee TM, Lin MS, Chang NC. Inhibition of histone deacetylase on ventricular remodeling in infarcted rats. Am J Physiol Heart Circ Physiol. 2007;293:H968–77.CrossRefGoogle Scholar
  73. 73.
    Kee HJ, Kook H. Krüppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy. J Mol Cell Cardiol. 2009;47:770–80.CrossRefGoogle Scholar
  74. 74.
    Ma P, Pan H, Montgomery RL, Olson EN, Schultz RM. Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during myocyte development. Proc Natl Acad Sci U S A. 2012;109:E481–9.Google Scholar
  75. 75.
    Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 2007;100:416–24.CrossRefGoogle Scholar
  76. 76.
    Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13:613–8.CrossRefGoogle Scholar
  77. 77.
    Dispersyn GD, Geuens E, Ver Donck L, Ramaekers FC, Borgers M. Adult rabbit cardiomyocytes undergo hibernation-like dedifferentiation when co-cultured with cardiac fibroblasts. Cardiovasc Res. 2001;51:230–40.CrossRefGoogle Scholar
  78. 78.
    Szibor M, Pöling J, Warnecke H, Kubin T, Braun T. Remodeling and dedifferentiation of adult cardiomyocytes during disease and regeneration. Cell Mol Life Sci. 2014;71:1907–16.CrossRefGoogle Scholar
  79. 79.
    Jopling C, Sleep E, Raya M, Martí M, Raya A, Izpisúa Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464:606–9.CrossRefGoogle Scholar
  80. 80.
    Taegtmeyer H. From fetal to fatal. In: Cokkinos DV, Pantos C, Heusch G, Taegtmeyer H, editors. Myocardial ischemia. New York: Springer; 2006. p. 1–9.Google Scholar
  81. 81.
    Razeghi P, Taegtmeyer H. Cardiac remodeling: UPS lost in transit. New York. Circ Res. 2005;97:964–6.Google Scholar
  82. 82.
    Baskin KK, Taegtmeyer H. Taking pressure off the heart: the ins and outs of atrophic remodelling. Cardiovasc Res. 2011;90:243–50.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Heart and Vessel DepartmentBiomedical Research Foundation, Academy of Athens - Gregory SkalkeasAthensGreece

Personalised recommendations