Early Developmental Risk for Adult Cardiovascular Disease: High risk Subgroups, Biomarkers, and Mechanisms

This project seeks to generate new insights – of clinical and public/health/relevance – regarding the early identification and prevention of adult coronary heart disease (CHD). It is well known that 10% of infants born small for gestational age (SGA), compared to average for gestational infants (AGA), are at increased risk for later life CHD and cardiovascular disease (CVD)

mortality. However, there is substantial heterogeneity in these findings and it is not clear: a) which SGA infants are at elevated risk; and b) which underlying pathobiologic mechanisms are implicated. Based upon our published work and those of others, we hypothesize that fetal programming related to placental dysfunction, chronic fetal hypoxia, nutrient deprivation and

cardiac remodeling in some SGA infants results in cardiovascular and metabolic alterations and subsequent increased CHD risk. Understanding which SGA infants are at elevated risk, and by what mechanisms are critical steps to advance prevention efforts through targeted screening and early intervention practices.

The New England Family Study (NEFS) is a prenatal cohort of 16,000 individuals now aged 57- 64-years, offspring of pregnant women enrolled in the Providence, RI and Boston, MA sites of the NIH Collaborative Perinatal Project. Participants were recruited between 1959 and 1966, prenatal and infant umbilical cord serum samples collected, and offspring assessed through the

first 7-years of life, providing a unique cohort to address these topics. Our multidisciplinary team with an established collaborative track record proposes to complete comprehensive clinical assessments of approximately 800 SGA infants from this cohort. We will be able to conduct this 60-year prospective project - with state-of-the-art adult cardiovascular assessments - based

upon 35-years fieldwork with this cohort and prior experience of clinical assessments with large samples of community participants. Using banked maternal and infant sera, we will evaluate prenatal (mother’s 3rd trimester) serum for markers of: a) placental dysfunction and impaired vasculogenesis (placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1

(SFLT-1) / PGIF ratio and b) metabolomics as evidence of maternal metabolic programming – in relation to adult offspring CHD risk. Using cord serum samples, we will investigate evidence of chronic fetal hypoxia (erythropoietin levels), lipids, and metabolomics as measures of metabolic programming and fetal NT-pro-BNP and hs-TcNT-T as reflective of cardiac programming in

SGA infants – in relation to adult offspring CVD risk. Plans and implications detailed herein. Project Summary/Abstract