Placental insufficiency appears to be an important cause of fetal undergrowth in conditions ranging from preeclampsia to asymmetrical intrauterine growth retardation. Fetal undergrowth is associated with a significantly increased risk adult onset coronary artery disease. Recent data show that low term birthweight is also associated with ventricular wall thickening and a reduction in coronary artery diameter. It is likely that the undergrown heart will be less able to perform systolic work in the face of increased arterial pressures at birth and it may not be able to generate a normal complement of cardiomyocytes during postnatal life. If the heart of a fetus develops under the conditions of placental insufficiency plus hypertension, it has an additional problem. We hypothesize that it will increase its myocyte numbers but will also prematurely allocate cells to the terminal differentiation pathway and will not be able to regenerate cells after birth. The outcome will be a hypertrophied heart with larger but fewer cells during postnatal life. Such hearts, as shown for adult rats that were hypoxemic before birth, will have a smaller capillary network, fewer but larger overworked cardiomyocytesand will be more vulnerable to coronary disease and heart failure. We hypothesize that placental pathology leads to hypoxemia and glucocorticoid (cortisol) excess and then to heart pathology. Excess cortisol binds the mineralocorticoid receptor-- which leads to loss of compliance through fibrosis, decreases contractility, and stunts coronary arterial growth. Umbrella hypothesis: the patterns of growth and development of the fetal myocardium, during a fetal placental embolization, are determined by the resulting hemodynamic and corticosteroid environment in which the heart develops. We will test this premise through 4 aims.
Aim 1 : To characterize the patterns of cardiomyocytegrowth and maturation under conditions of placental insufficiency in two groups that differ by their degree of reactive hypertension.
Aim 2 : To determine the functional characteristics of hearts developing under conditions of placental insufficiency.
Aim 3 : To determine roles of corticosteroid hormones in regulating myocyte growth and development.
Aim 4 : To determine postnatal growth patterns of hearts that developed under conditions of placental insufficiency.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD034430-15
Application #
8307354
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
15
Fiscal Year
2011
Total Cost
$202,126
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Kolahi, Kevin S; Valent, Amy M; Thornburg, Kent L (2017) Cytotrophoblast, Not Syncytiotrophoblast, Dominates Glycolysis and Oxidative Phosphorylation in Human Term Placenta. Sci Rep 7:42941
Midgett, Madeline; Thornburg, Kent; Rugonyi, Sandra (2017) Blood flow patterns underlie developmental heart defects. Am J Physiol Heart Circ Physiol 312:H632-H642
Wallace, Alexandra H; Dalziel, Stuart R; Cowan, Brett R et al. (2017) Long-term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study. Arch Dis Child 102:40-45
Jonker, S S; Louey, S (2016) Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment. J Endocrinol 228:R1-18
Burton, Graham J; Fowden, Abigail L; Thornburg, Kent L (2016) Placental Origins of Chronic Disease. Physiol Rev 96:1509-65
Barry, James S; Rozance, Paul J; Brown, Laura D et al. (2016) Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction. Exp Biol Med (Maywood) 241:839-47
Thornburg, Kent L; Kolahi, Kevin; Pierce, Melinda et al. (2016) Biological features of placental programming. Placenta 48 Suppl 1:S47-S53
Chadderdon, Scott M; Belcik, J Todd; Bader, Lindsay et al. (2016) Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance. Diabetes 65:2249-57
Kolahi, Kevin; Louey, Samantha; Varlamov, Oleg et al. (2016) Real-Time Tracking of BODIPY-C12 Long-Chain Fatty Acid in Human Term Placenta Reveals Unique Lipid Dynamics in Cytotrophoblast Cells. PLoS One 11:e0153522
Jonker, Sonnet S; Davis, Lowell; Soman, Divya et al. (2016) Functional adaptations of the coronary microcirculation to anaemia in fetal sheep. J Physiol 594:6165-6174

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