Congenital heart disease significantly alters the normal growth and development of the fetus. Furthermore, fetuses with congenital heart disease have excessively high in utero and perinatal morbidity that may be related to impaired fetal systemic and myocardial hemodynamics. Adaptation of the fetal heart to a pressure load or chronic anemia, as occurs with a number of congenital heart lesions or fetal pathologic states, results in an increase in ventricular mass. Little is known on how the overloaded fetal heart adapts its microvasculature and metabolic pathways to accommodate the increase energetic demands of the myocardium. These compensatory myocardial responses likely have a major influence on both immediate and long term survival. In the adult heart, the molecular and morphologic changes that accompany the hypertrophic response have been extensively studied and include reactivation of a number of """"""""fetal"""""""" pathways. However, in the fetal heart, the molecular triggers for increasing ventricular mass and the accompanying vascular and metabolic responses are poorly understood. Our preliminary data obtained in fetal sheep demonstrate that during the third trimester of gestation there are developmental changes in the expression of a number of genes that are likely important in regulating the vascular and metabolic response of the overloaded heart. The immediate goals of the studies outlined in this proposal are: (1) to determine the molecular and morphologic basis of microvascular and metabolic adaptations of the fetal heart as it increases in mass following the imposition of clinically important stimuli; (2) to investigate how these responses are regulated at different stages of fetal development. Information gained from these studies will improve our understanding of the compensatory changes of the overloaded fetal myocardium and help direct new investigations related to returning the heart to more """"""""normal"""""""" physiology. The end result is hoped to be that the infant with a more 'normal' heart and circulatory physiology will have improved survival with less morbidity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064770-02
Application #
6537789
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Pearson, Gail D
Project Start
2001-07-15
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$367,500
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Freise, Kevin J; Widness, John A; Segar, Jeffrey L et al. (2007) Increased erythropoietin elimination in fetal sheep following chronic phlebotomy. Pharm Res 24:1653-9
Olson, Aaron K; Protheroe, Kristin N; Segar, Jeffrey L et al. (2006) Mitogen-activated protein kinase activation and regulation in the pressure-loaded fetal ovine heart. Am J Physiol Heart Circ Physiol 290:H1587-95
Olson, Aaron K; Protheroe, Kristen N; Scholz, Thomas D et al. (2006) The mitogen-activated protein kinases and Akt are developmentally regulated in the chronically anemic fetal sheep heart. J Soc Gynecol Investig 13:157-65
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Nau, Peter N; Van Natta, Timothy; Ralphe, J Carter et al. (2002) Metabolic adaptation of the fetal and postnatal ovine heart: regulatory role of hypoxia-inducible factors and nuclear respiratory factor-1. Pediatr Res 52:269-78