Cardiovascular disease is the leading cause of death in the developed world. Epidemiological studies have shown the profound importance that the prenatal period has on life-long health. A likely explanation for this relationship is that the late fetal period, a period of robust growth, determines the number of cardiomyocytes and the structure of the coronary vasculature for life. Adverse intrauterine conditions leading to fetal growth restriction alter cardiac load and compromise heart growth. While the ability of adult heart to adapt to cardiovascular disease is limited, the fetal heart is highly plastic, undergoing rapid adaptation to best meet intrauterine conditions. The number of fetal cardiomyocytes and the anatomical dimensions of the fetal coronary circulation are not fixed but can be changed, both up and down, by prenatal conditions. Unfortunately, fetal responses to sub-optimal intrauterine environments may not lead to favorable outcomes in the fetus or later in the adult. It will not be possible to understand the devastating effects of intrauterine growth retardation on the fetal myocardium unless we deliberately study cardiomyocyte and coronary microvascular growth in a well controlled experimental load model. The overarching hypothesis of the proposal is that fetal heart growth is exquisitely sensitive to hemodynamic load and that altered growth leads to irreversible changes in cardiac myocyte and coronary vascular function for life. The proposed experiments will demonstrate for the first time the precise responses that determine how the fetal heart adapts to changes in loading conditions during late gestation when all the terminal maturation processes are underway. Completion of the proposed work will provide a clearer understanding of the relationship between fetal cardiomyocyte and coronary vascular growth, how this interrelationship affects fetal cardiac function, which changes persist into adulthood and how adult heart function is affected. This work is an essential step in understanding the mechanisms responsible for the association between fetal growth restriction and adult cardiovascular disease.
Cardiovascular disease accounts for the majority of morbidity and mortality in both the young and the old. There is irrefutable evidence of the fetal origins of adult cardiovascular disease. Knowledge of both normal and abnormal fetal cardiac growth, and how changes influence adult heart disease, is essential to the development of new strategies in perinatal medicine and in treating cardiovascular disease throughout life.
|Chattergoon, N N; Louey, S; Stork, P J et al. (2014) Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes. Am J Physiol Heart Circ Physiol 307:H1216-25|
|Rinkevich, Diana; Belcik, Todd; Gupta, Nandita C et al. (2013) Coronary autoregulation is abnormal in syndrome X: insights using myocardial contrast echocardiography. J Am Soc Echocardiogr 26:290-6|
|Thornburg, Kent L; Louey, Samantha (2013) Uteroplacental circulation and fetal vascular function and development. Curr Vasc Pharmacol 11:748-57|
|Anderson, Debra F; Jonker, Sonnet S; Louey, Samantha et al. (2013) Regulation of intramembranous absorption and amniotic fluid volume by constituents in fetal sheep urine. Am J Physiol Regul Integr Comp Physiol 305:R506-11|
|Fan, L; Lindsley, S R; Comstock, S M et al. (2013) Maternal high-fat diet impacts endothelial function in nonhuman primate offspring. Int J Obes (Lond) 37:254-62|
|Chattergoon, Natasha N; Giraud, George D; Louey, Samantha et al. (2012) Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J 26:397-408|
|Bernard, Leah S; Hashima, Jason N; Hohimer, A Roger et al. (2012) Myocardial performance and its acute response to angiotensin II infusion in fetal sheep adapted to chronic anemia. Reprod Sci 19:173-80|
|Back, Stephen A; Riddle, Art; Dean, Justin et al. (2012) The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359-70|
|Chattergoon, Natasha N; Louey, Samantha; Stork, Philip et al. (2012) Mid-gestation ovine cardiomyocytes are vulnerable to mitotic suppression by thyroid hormone. Reprod Sci 19:642-9|
|Thornburg, Kent; Jonker, Sonnet; O'Tierney, Perrie et al. (2011) Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol 106:289-99|
Showing the most recent 10 out of 67 publications