Kent L. Thornburg

Effect of in utero and early-life conditions on adult health and disease.

Many lines of evidence, including epidemiologic data and extensive clinical and experimental studies, indicate that early life events play a powerful role in influencing later susceptibility to certain chronic diseases. This review synthesizes evidence from several disciplines to support the contention that environmental factors acting during development should be accorded greater weight in models of disease causation.

Pre-Eclampsia Is Associated With Increased Risk of Stroke in the Adult Offspring: The Helsinki Birth Cohort Study

Background and Purpose— Women who develop pre-eclampsia in pregnancy are at increased risk of cardiovascular disease. The offspring from pregnancies complicated by pre-eclampsia have higher blood pressures during childhood, but little is known about their long-term health. We hypothesized that pre-eclampsia would lead to an increased risk of cardiovascular disease in the offspring. Methods— We traced 6410 babies born in Helsinki, Finland, from 1934 to 1944. We used the mothers’ blood pressure levels and the presence of proteinuria during pregnancy to define pre-eclampsia and gestational hypertension without proteinuria according to modern criteria. Results— Two hundred eighty-four of the pregnancies were complicated by pre-eclampsia (120 with nonsevere and 164 with severe disease) and 1592 by gestational hypertension. The crude hazard ratio for all forms of stroke among people whose mothers had pre-eclampsia was 1.9 (1.2 to 3.0; P=0.01); among people whose mothers had gestational hypertension, it was 1.4 (1.0 to 1.8; P=0.03). There was no evidence that these pregnancy disorders were associated with coronary heart disease in the offspring. Pre-eclampsia, in particular severe disease, was associated with a reduced mean head circumference at birth, whereas gestational hypertension was associated with an increased head circumference in relation to body length. Conclusions— People born after pregnancies complicated by pre-eclampsia or gestational hypertension are at increased risk of stroke. The underlying processes may include a local disorder of the blood vessels of the brain as a consequence of either reduced brain growth or impaired brain growth leading to “brain-sparing” responses in utero.

Hemodynamic changes in pregnancy

The basic mechanisms that underlie alterations in the physiology of pregnancy are virtually unknown. Basal oxygen consumption increases by some 50 mL/min in pregnant women at term. Blood volume increases gradually over gestation as does red cell mass. Cardiac output increases by some 50% by mid-third trimester. Stroke volume and heart rate increase over the course of pregnancy with heart rate increasing gradually until term. The heart of the pregnant woman remodels dramatically in the first few weeks of pregnancy; end diastolic volume increases. Stroke volume is augmented by the increase in end diastolic volume and maintenance of ejection fraction through a possible increase in contractile force. Systolic and diastolic blood pressures drop during normal pregnancy. There is evidence of blood vessel remodeling in all vessels. Venous compliance and venous blood volume are increased. Renal plasma flow increases by some 70% in pregnancy with glomerular filtration rate increasing by 50% by unknown mechanisms. The complex hormonal environment is changing throughout pregnancy. In summary, under the influence of circulating chemical mediators blood flow is redistributed to the uterus, breast, and kidney.

Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition

Prepregnancy maternal obesity confers an increased risk of stillbirth, but the mechanisms are unknown. Maternal obesity is associated with placental inflammation. We considered that maternal diet may predispose to the increased risk of placental inflammation and stillbirth. We hypothesized that a chronic high-fat diet (HFD) is associated with abnormal uteroplacental circulation and placental inflammation. Here we used a nonhuman primate model to determine the effect of chronic HFD on the uterine and placental hemodynamics, placental histology, and inflammation in a prospective, observational study of 24 Japanese macaques. Overall, there was a statistically significant (38-56%) reduction in uterine volume blood flow from HFD animals, whether they were lean or obese. Consumption of a HFD, independent of obesity, increased placental inflammatory cytokines and the expression of Toll-like receptor 4. We show that HFD consumption by obese mothers with hyperinsulinemia also reduced volume blood flow on the fetal side of the placenta and significantly increased the frequency of both placental infarctions and stillbirth. These results suggest that a HFD, independent of obesity, decreases uterine volume blood flow. Maternal obesity and insulin resistance further exacerbates the placental dysfunction and results in an increased frequency of stillbirth.

The surface area of the placenta and hypertension in the offspring in later life

Hypertension is more common among people who had low birthweight. Birthweight depends on the mothers body size and on the growth of the placenta. We studied a group of 2003 subjects, of whom 644 were being treated for hypertension. They were born during 1934-44 in a hospital that kept detailed records of maternal and placental size. Hypertension was associated with reduced placental weight and surface area. These associations were strongest in the offspring of mothers with below average height or low socioeconomic status. In people whose mothers had below average height (160 cm) the prevalence of hypertension fell from 38% if the placental area was 200 cm(2) or less to 21% if the area was more than 320 cm(2) (p=0.0007). In the offspring of tall, middle class mothers, who were likely to have been the best nourished, hypertension was predicted by large placental weight in relation to birthweight. The odds ratio rose from 1.0 if the ratio of placental weight to birthweight was 0.17 or less to 1.9 (95% confidence interval 0.8 to 5.0) if the ratio was more than 0.21 (p for trend =0.03). We conclude that the effects of placental area on hypertension depend on the mothers nutritional state. Poor maternal nutrition may compound the adverse effects of small placental size. In better-nourished mothers the placental surface may expand to compensate for fetal undernutrition. Growth along the minor axis of the surface may be more nutritionally sensitive than growth along the major axis.

Placental programming of chronic diseases, cancer and lifespan: A review

Particular paths of fetal growth are now known to predict a range of disorders in adult life. This is thought to reflect fetal programming, the phenomenon whereby nutrition and other influences during development set the bodys organs and systems for life. The thesis of this review is that normal variations in the processes of placental development lead to variations in the supply of nutrients to the fetus and programme a small number of key systems that are linked to later disease. A babys growth and nutrition depend both on the function of the placenta, reflected in its gross morphology at birth, and on the mothers lifetime nutrition, reflected in her height and weight. In many studies, the effects of placental size and shape on later disease have been examined within different categories of mothers body size. The review shows that variations in gross placental morphology at birth predict a wide range of disorders in later life. Any particular placental phenotype seems to predict a limited number of diseases. Further research into the links between the processes of placentation and the morphology of the placenta at birth is now required. We need to know more about the relative importance of nutrient flow, nutrient balance and the timing of nutritional events in determining disorders in later life. We also need to understand why, compared to other placental mammals, the human placenta is so variable in its morphology and functional capacity.

The early origins of chronic heart failure: impaired placental growth and initiation of insulin resistance in childhood

Low birth weight and low placental weight predict later coronary heart disease and hypertension. This has led to the hypothesis that these diseases are initiated by foetal programming, the process by which foetal malnutrition leads to permanent changes in the body in ways that lead to chronic disease in later life. Here we examine the association between body and placental size at birth and later chronic heart failure.

The Obstetric Origins of Health for a Lifetime

There is a new “developmental” model for the origins of a wide range of chronic diseases. Under this model the causes to be identified are linked to normal variations in fetoplacental development. These variations are thought to lead to variations in the supply of nutrients to the baby that permanently alter gene expression, a process known as “programming.” According to the developmental model variations in the processes of development program the function of a few key systems that are linked to disease, including the immune system, antioxidant defenses, inflammatory responses, and the number and quality of stem cells.

Meeting Report on the 3rd International Congress on Developmental Origins of Health and Disease (DOHaD)

Developmental origins of health and disease (DOHaD) focuses on the earliest stages of human development, and provides a novel paradigm to complement other strategies for lifelong prevention of common chronic health conditions. The 3rd International Congress on DOHaD, held in 2005, retained the most popular features from the first two biannual Congresses, while adding a number of innovations, including increased emphasis on implications of DOHaD for the developing world; programs for trainees and young investigators; and new perspectives, including developmental plasticity, influences of social hierarchies, effects of prematurity, and populations in transition. Emerging areas of science included, first, the controversial role of infant weight gain in predicting adult obesity, diabetes, and cardiovascular disease. Second, in the era of epidemic obesity, paying attention to the over-nourished fetus is as important as investigating the growth retarded one. Third, environmental toxins appear to have abroad range of long-lasting effects on the developing human. Fourth, epigenetic mechanisms could unite several strands of human and animal observations, and explain how genetically identical individuals raised in similar postnatal environments can nonetheless develop widely differing phenotypes. Improving the environment to which an individual is exposed during development may be as important as any other public health effort to enhance population health world wide.

Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes

Rat and sheep cardiac myocytes become binucleate as they complete the ‘terminal differentiation’ process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5‐bromo‐2′‐deoxyuridine (BrdU) uptake) separately in mono‐ vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II‐stimulated cells and prevented cell hypertrophy in PE‐stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.