The Influence of Early Programming in the Development of Cardiovascular, Lung, Blood, and Sleep Disorders

Discussion:

Epidemiologic observations by David Barker in the late1980s indicated that babies born before World War II in Hertfordshire, England, who had low birth weights, entered adulthood with an increased risk of cardiovascular disease (CVD). The "Barker Hypothesis" suggests that changes in the intrauterine environment can alter organ development and "program" physiological systems in the developing fetus, leading to an increased risk for a wide variety of diseases later in life. The WG discussed the need for more data on basic biological mechanisms to better understand how intrauterine challenges modify and program: (1) development of organ systems (heart, systemic vasculature, brain, placental vasculature, and kidney), (2) specific physiological pathways, and (3) phenotypes and gene-environment interactions. They discussed the importance of determining critical times during development when an organ system is susceptible to intrauterine challenges and of elucidating mechanisms that increase vulnerability. Identifying biomarkers (maternal and fetal) is also necessary for validating clinical manifestations and for developing early interventions. Alterations in placenta and placental signaling were discussed, since changes in the placenta itself, and in the placental barrier, milieu, and vasculature during intrauterine challenges may well determine the functionality of organs and cardiovascular or lung vulnerability.

The Working Group indicated that better clinical endpoints are needed. Other measurements of neonatal body composition (e.g., adiposity) and the metabolic and endocrine milieu, in addition to birth weight, might turn out to be good predictors of CVD in adulthood. New epidemiological studies are needed because the current state of knowledge is based on old data that may have little relevance to today's situation. In recent decades, the incidence and prevalence of obesity, diabetes, peripheral vascular disease, pre-hypertension, hypertension, and dyslipidemias, as well as bio-behavioral stress and depression have increased in the general population and, particularly, in women. Therefore, new research and approaches on preventing and treating these CVD risk factors are needed.

Recommendations:

The Working Group made the following prioritized recommendations:

1. Investigate the effects of the intrauterine environment on the developing heart (e.g., increased placental resistance, heart loading, and development of the coronary tree), brain (e.g., factors that regulate proliferation, differentiation, and migration of cells in areas associated with regulation of sleep and cardiac function) and kidney (e.g., factors that regulate the normal production of each segment of the tubular unit)
2. Evaluate the effects of a sub-optimal intrauterine environment on the placental supply line and how placental modifications affect development and function of blood vessels, heart, and lung.
3. Determine mechanisms by which alterations in the intrauterine environment predispose to the development of asthma in adulthood, including the pathophysiology of cytokine function and programming of immune responses.
4. Identify (in mother, fetus, and offspring) markers of abnormal development that are predictive of adult-onset cardiovascular, lung, and blood disorders.
5. Building on the Barker Hypothesis, design prospective epidemiological studies to identify better measures that correlate with clinical manifestations of heart, lung, and blood diseases.
6. Develop new animal models and refine old ones to evaluate phenotypes and development of physiological pathways (e.g., the sympathetic nervous system).
7. Investigate nutritional, hormonal, and neural factors that regulate appropriate angiogenesis to promote optimal growth of tissues.
8. Evaluate socio-economic factors that can influence the intrauterine environment and result in disparities in health outcomes.

The Working Group also made some recommendations in areas outside the mission of the NHLBI:

• Characterize the sequence of effects of gestational diabetes and/or obesity in mothers on the health of the offspring (e.g., whether insulin resistance precedes obesity or vice versa in mothers and their offspring who are predisposed to diabetes).
• Investigate the interaction of genomic variation and obesity-related outcomes.
• Determine the role of periconceptual events used in assisted reproductive techniques.
• Understand the special challenges of teenage development in young women and of teenage pregnancy, in particular. Evaluate the associated social factors, such as maternal psychological stress. Educate women (and men) who cannot believe they are at risk on the nature of the risk and its consequences.

NHLBI Contact:

Cristina Rabadan-Diehl, Ph.D., NHLBI, NIH
rabadanc@mail.nih.gov

Working Group Members

Chair:

• Peter Nathanielsz, Ph., M.D., D.Sc., University of Texas Health Science Center

Members:

• Matthew W. Gillman, MD, S.M., Harvard Medical School
• Wulf Palinski, M.D., University of California, San Diego
• David Phillips, B.A., Southampton General Hospital
• Lucilla Poston, Ph.D., King’s College London
• Lawrence P. Reynolds, Ph.D., North Dakota State University
• David Siscovick, M.D., M.P.H., University of Washington
• Kent L. Thornburg, Ph.D., Oregon Health and Sciences University