NHLBI Working Group
The Influence of Early Programming in the Development of Cardiovascular,
Lung, Blood, and Sleep Disorders
September 27, 2005
The National Heart, Lung, and Blood Institute convened a Working Group
on September 27, 2005, in Bethesda, Maryland to assess and identify opportunities
for research on how the intrauterine environment affects the development
of heart, lung, blood, and sleep disorders later in life. Experts in developmental
biology, developmental physiology, animal models, and in cardiovascular,
lung, and blood diseases were invited to participate. The working group
meeting was preceded by a workshop, The Intrauterine Environment: Long
Term Consequences for Obesity and Metabolic Disorders (http://www.niddk.nih.gov/fund/other/maternalobesity/)
sponsored by four NIH institutes (NIDDK, NHLBI, NICHD, and NIEHS), which
focused on the effect of maternal diabetes and obesity on metabolic diseases
in their offspring and augmented the ensuing working group 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.
The Working Group made the following prioritized recommendations:
- 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)
- 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.
- 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.
- Identify (in mother, fetus, and offspring) markers of abnormal development
that are predictive of adult-onset cardiovascular, lung, and blood disorders.
- Building on the Barker Hypothesis, design prospective epidemiological
studies to identify better measures that correlate with clinical manifestations
of heart, lung, and blood diseases.
- Develop new animal models and refine old ones to evaluate phenotypes
and development of physiological pathways (e.g., the sympathetic nervous
- Investigate nutritional, hormonal, and neural factors that regulate
appropriate angiogenesis to promote optimal growth of tissues.
- 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
- Determine the role of periconceptual events used in assisted reproductive
- 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.
Cristina Rabadan-Diehl, Ph.D., NHLBI, NIH
Working Group Members
Chair: Peter Nathanielsz, Ph., M.D., D.Sc., University of Texas Health Science Center
- 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
Last updated: February 13, 2006