Cardiovascular disease remains the number one killer in western nations in spite of declines in death rates following improvements in clinical care. It has been 20 years since David Barker and colleagues showed that slow rates of prenatal growth predict mortality from ischemic heart disease. Thus, fetal undergrowth and its associated cardiovascular diseases must be due, in part, to placental inadequacies. This conclusion is supported by a number of studies linking placental characteristics with various adult diseases. A "U" shaped relationship between placental-to-fetal weight ratio and heart disease provides powerful evidence that placental growth-regulating processes initiate vulnerabilities for later heart disease in offspring. Recent evidence from Finland indicates that placental morphological characteristics predict risks for coronary artery disease, heart failure, hypertension and several cancers. The level of risk imparted by placental shape is sex dependent. Further, maternal diet and body composition strongly influence placental growth, levels of inflammation, nutrient transport capacity and oxidative stress, with subsequent effects on offspring health. Several animal models have demonstrated the placental roots of vulnerability for heart disease. These include findings that abnormal endothelial development in the placenta is associated with undergrown myocardial walls in the embryo, and that placental insufficiency leads to depressed maturation and proliferation of working cadiomyocytes in the fetal heart. Together these models suggest that the ultimate fitness of the heart is determined by hemodynamic, growth factor, and oxygen/nutrient cues before birth, all of which are influenced, if not regulated by the placenta.

During fetal life the myocardium expands through replication of cardiomyocytes. In sheep, cardiomyocytes begin the process of becoming terminally differentiated at about 100 gestation days out of 145 days term. In this final step of development, cardiomyocytes become binucleated and stop dividing. The number of cells at birth is important in determining the number of cardiomyocytes for life. Therefore, the regulation of cardiomyocyte growth in the womb is critical to long term disease outcome. Growth factors that stimulate proliferation of fetal cardiomyocytes include angiotensin II, cortisol and insulin-like growth factor-1. Increased ventricular wall stress leads to short term increases in proliferation but longer term loss of cardiomyocyte generative capacity. Two normally circulating hormones have been identified that suppress proliferation: atrial natriuretic peptide (ANP) and tri-iodo-L-thyronine (T3). Atrial natriuretic peptide signals through the NPRA receptor that serves as a guanylate cyclase and signals through cGMP. ANP powerfully suppresses mitotic activity in cardiomyocytes in the presence of angiotensin II in culture. Addition of a cGMP analogue has the same effect as ANP. ANP suppresses both the extracellular receptor kinases and the phosphoinositol 3 kinase pathways. T3 also suppresses increased mitotic activity of stimulated cardiomyocytes but does so by increasing the cell cycle suppressant, p21, and decreasing the cell cycle activator, cyclin D1.

Few studies have examined whether the duration of breast-feeding is associated with BMI in adult life. In the past, the heights and weights of infants and the duration of breast-feeding were routinely recorded at infant welfare clinics in Helsinki, Finland. Most infants in the city were taken to these free clinics. The Helsinki Birth Cohort comprises 13,345 people born in the city during 1934-1944; 84% were breast-fed. In 2001, a questionnaire was sent to members of the cohort asking about their weight and height. A random sample of 2003 men and women attended a clinic at which height, weight, and body composition were measured. We studied sibships that included 2 or more people from the cohort. There were 1823 subjects: 831 had completed the questionnaire; 129 had attended the clinic. We grouped the subjects according to duration of breast-feeding: 0-2 mo, 3-4 mo, 5-7 mo, and 8 mo or more. We compared siblings who were discordant for duration of breast-feeding. We found that a longer period of breast-feeding was associated with lower BMI at 1 y of age (P = 0.04 for a linear trend). This relation disappeared by the age of 7 y. People breast-fed for 5-7 mo had the lowest reported BMI at age 60 y, although this was not statistically significant; 8.8% more people breast-fed for 8 mo or more had reported BMIs that were overweight (25 to 30 kg/m(2)) compared with those breast-fed for shorter periods (P = 0.06). Breast-feeding for <2 mo or 8 mo or more was associated with an increased BMI and percentage body fat in later life, measured at the clinic (P = 0.08 and P = 0.03 for quadratic trends). We conclude that breast-feeding for <2 mo may be deleterious, possibly because of lack of exposure to protective factors in breast milk. Breast-feeding beyond 8 mo may be deleterious because mother's hormones in breast milk reset the infant's hypothalamic-pituitary-thyroid axis.

The role of atrial natriuretic peptide (ANP) in regulating fetal cardiac growth is poorly understood. Angiotensin II (Ang II) stimulates proliferation in fetal sheep cardiomyocytes when growth is dependent on the activity of the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3K) pathways. We hypothesized that ANP would suppress near-term fetal cardiomyocyte proliferation in vitro and inhibit both the MAPK and PI3K pathways. Forty-eight hour 5-bromodeoxyuridine (BrdU) uptake (used as an index of proliferation) was measured in cardiomyocytes isolated from fetal sheep ( Abbreviations Ang II, angiotensin II; ANP, atrial natriuretic peptide; BrdU, 5-bromodeoxyuridine; cGMP, cyclic guanosine monophosphate; CMC, cardiomyocyte; ERK, extracellular signal-regulated kinase; IGF-1, insulin-like growth factor-1; LV, left ventricle; MAPK, mitogen-activated protein kinase; MKP-1, MAPK phosphatase-1; NPRA, natriuretic peptide receptor type A; PI3K, phosphoinositol-3 kinase; RV, right ventricle.

The fetal heart is highly sensitive to changes in mechanical load. We have previously demonstrated that increased cardiac load can stimulate cell cycle activity and maturation of immature cardiomyocytes, but the effects of reduced load are not known. Sixteen fetal sheep were given either continuous intravenous infusion of lactated Ringer solution (LR) or enalaprilat, an angiotensin-converting enzyme inhibitor beginning at 127 days gestational age. After 8 days, fetal arterial pressure in the enalaprilat-infused fetuses (23.8 +/- 2.8 mmHg) was lower than that of control fetuses (47.5 +/- 4.7 mmHg) (P < 0.0001). Although the body weights of the two groups of fetuses were similar, the heart weight-to-body weight ratios of the enalaprilat-infused fetuses were less than those of the LR-infused fetuses (5.6 +/- 0.5 g/kg vs. 7.0 +/- 0.6 g/kg, P < 0.0001). Dimensions of ventricular myocytes were not different between control and enalaprilat-infused fetuses. However, there was a significant decrease in cell cycle activity in both the right ventricle (P < 0.005) and the left ventricle (P < 0.002) of the enalaprilat-infused fetuses. Thus, we conclude a sustained reduction in systolic pressure load decreases hyperplastic growth in the fetal heart.