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.
|Effective start/end date||2/15/00 → 7/31/03|
- National Institutes of Health: $73,462.00
- National Institutes of Health: $74,798.00