Ventricular hypertrophy/dilation is a precursor to cardiac failure - the most significant cause of morbidity and mortality in American adults. There may well be """"""""premorbid determinants"""""""" of ventricular function with some individuals poised genetically to respond more or less effectively to a pathologically induced load or to normal aging. Alternatively, recent epidemiological studies suggest that there is perinatal environmental """"""""programming"""""""" of the adult cardiovascular system. We will test the general hypothesis that perinatal hypoxic stress will alter adult ventricular size, shape or performance and that some of these effects are gender specific. Preliminary data in newborn mice subjected to ambient hypoxia indicate not only dramatic right ventricular (RV) but also left ventricular (LV) hypertrophy and there are residual effects on the hearts of young adults. Both sexes retained significant RV hypertrophy but there are gender specific effects on LV size and function assayed by transthoracic echocardiography. While these residual effects are not large or physiologically debilitating in young adults, we hypothesize that they are the basis of more severe pathology that will be seen-with increasing age or when additional afterload or growth stresses are applied in adulthood. Atrial natriuretic peptide is expressed in the hypertrophying adult or newborn ventricle and appears to act as an autocrine/paracrine molecular """"""""brake."""""""" We expect that mice genetically lacking the atrial natriuretic peptide type A receptor will respond to a perinatal stress with excessive ventricular hypertrophy and subsequently a more severe adult dysfunction. The coupling of genetic tools and constructs available in the mouse with traditional physiologic and anatomical approaches offers the potential to test molecular hypotheses at the organ and whole animal level. Each organism's genetic program undoubtably interacts with early environmental stresses to influence adult morphology and function as well as susceptibility to disease and aging.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD038495-01
Application #
6039474
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Wright, Linda
Project Start
2000-02-15
Project End
2003-01-31
Budget Start
2000-02-15
Budget End
2002-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$73,462
Indirect Cost
Name
Oregon Health and Science University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Broberg, Craig S; Pantely, George A; Barber, Brent J et al. (2003) Validation of the myocardial performance index by echocardiography in mice: a noninvasive measure of left ventricular function. J Am Soc Echocardiogr 16:814-23