Cardiovascular disease in fetal alcohol spectrum disorder

Project Summary
The incidence of congenital heart defects (CHDs) and cardiovascular disease (CVD) in patients with fetal alcohol
spectrum disorder (FASD) are poorly characterized. Cardiovascular abnormalities may be common in FASD;
however, comprehensive retrospective studies on lifetime CVD risk in adult patient cohorts have yet to be
performed. Cellular and molecular mechanisms underlying FASD-mediated CHD and CVD are also largely
unknown along with any biomarkers that would allow the patient population to be stratified based on CVD risk.
Here we present preliminary data from our retrospective clinic cohort that demonstrate that females with FASD
have an overall increase in CHD, myocardial infarction (MI) rate, and the likelihood of being diagnosed with any
CVD in adulthood. Females with FASD also have significantly reduced ejection fraction relative to matched
controls. These data suggest that FASD is a risk factor for CHD in newborns and CVD in adults. In a zebrafish
model of embryonic alcohol exposure (EAE), we confirmed a primary defect in cardiomyocyte migration that
causes subsequent functional and structural heart abnormalities, including contractility deficits and ventricular
wall abnormalities that persist through adulthood. Our findings indicate that EAE zebrafish can serve as a model
for lifelong cardiac function in the presence and absence of CHD. We propose three Specific Aims to test the
central hypothesis that FASD patients have an increased incidence of CVD and that the zebrafish EAE model
will uncover novel molecular mediators and biomarkers that explain and predict CVD risk. In Specific Aim 1, we
will perform a retrospective study to determine CVD incidence in an adult FASD patient cohort, including CHD,
hypertension, cardiomyopathy, MI, cerebrovascular accident, and embolism, as well as their association with
other metabolic and inflammatory conditions. In Specific Aim 2, we will define molecular mechanisms underlying
embryonic heart defects in a zebrafish EAE model by identifying and functionally evaluating the impact of
molecular alterations in migratory myl7+ cardiomyocytes that form the cardiac cone through hypothesis-driven
(PDGF pathway) and unbiased (bulk RNA-sequencing on FACS-isolated myl7+ cardiomyocytes) approaches.
In Specific Aim 3, we will test the hypothesis that EAE adults with a CHD are susceptible to cardiac dysfunction
and cardiomyopathy due to lasting alterations in cardiac structure, function, and molecular signature. Taken
together, the proposed studies will provide fundamental insights into the cardiovascular health outcomes of
patients with FASD, reveal novel molecular mediators of EtOH-induced CHDs, and identify biomarkers of adult
cardiac dysfunction in EAE adults. Cardiovascular diseases may contribute significantly to morbidity and
mortality in affected patients. By identifying which CVD outcomes impact FASD patients and what additional
metabolic and inflammatory factors indicate risk, we will provide an opportunity for early intervention. Further,
identification of molecular mediators of CHD and cardiomyopathy in a zebrafish model of EAE will allow us to
expand our mechanistic understanding of the effects of PAE across the lifespan.

Grant Number: 5U01AA030185-05
NIH Institute/Center: NIH
Principal Investigator: CAROLINE BURNS