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


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.

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Acetyl-CoA carboxylase


Protein kinase B


Atrial natriuretic factor


Specific insulin receptor knock out


Chicken ovalbumin upstream promoter transcription factor


Muscle carnitine palmitoyl transferase I


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


Fibroblast growth factor 2


Glucose, insulin, potassium


Glucose transporter 1


Glucose transporter 4


Glycogen synthase


Muscle glycogen synthase


Hypoxia inducible factor


Insulin-like growth factor 1


Janus kinases

MAP kinase:

Mitogen-activated protein kinase


Malonyl-CoA decarboxylase


Medium chain acyl-CoA dehydrogenase


Myocyte enhancer factor 2


Myosin heavy chain


Mammalian target of rapamycin


Nuclear factor of activated T cells


Pyruvate dehydrogenase complex


Pyruvate dehydrogenase kinase 2


Peroxisome proliferator activated receptor γ coactivator 1


Phosphatidylinositol 3 Kinase


Peroxisome proliferator activated receptor alpha


P70 ribosomal S6 kinase


Sarco (endo) plasmic reticulum Ca2+ATPase


Specificity protein 1/3


Serum response factor


Signal Transducers and Activators of Transcription


Thyroid receptor


Thyroid receptorα1


Thyroid receptorβ1


Uncoupling protein 3


Ubiquitin proteosome proteolytic


Ubiquitin proteasome system


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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.

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Correspondence to Heinrich Taegtmeyer.

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Rajabi, M., Kassiotis, C., Razeghi, P. et al. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12, 331–343 (2007).

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  • Fetal heart
  • Hypertrophy
  • Atrophy
  • Hibernating myocardium
  • Heart failure
  • Metabolism