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.
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